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Fang, Wenfeng, Xiuyu Cai, Huaqiang Zhou, Yinguang Wang, Yaxiong Zhang, Shaodong Hong, Yang Shao, and Li Zhang. "BRCA1/2 germline mutations and response to PARP inhibitor treatment in lung cancer." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e13007-e13007. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e13007.
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e13007 Background: Germline mutations in BRCA1/2 (BReast CAncer genes 1 and 2), which are targets for PARP inhibitors in breast and ovarian cancer, have been previously identified in patients with non-small cell lung cancer (NSCLC). However, its prevalence and clinical outcomes to targeted therapy in NSCLC still remains unknown. Methods: We conducted a retrospective review of 9,324 Chinese NSCLC patients who underwent targeted next-generation sequencing (NGS) during 2015/11/01 and 2018/10/31. Patients with BRCA1/2 somatic and germline mutations were identified. We summarized their prevalence and explored their co-existing driver mutations. Then we initially reviewed the response to PARP-inhibitor targeted therapy in patient with BRCA2 germline mutation. Results: 459 (4.9%) patients are BRCA1/2 positive (germline/somatic mutation). Most patients are diagnosed with LUAD (372, 81.1%), with a median age of 63 years (range: 2-101). Slightly more male patients were carrying BRCA1/2 mutations (59.9%, 275 out of 459). The prevalence of BRCA1 and BRCA2 somatic mutations was similar (145, 1.56% vs. 169, 1.81%, p = 0.19). BRCA2 germline mutation was more common in lung cancer than BRCA1 germline mutation (148, 1.59% vs. 20, 0.21%, p < 0.0001). When specified to the common driver gene mutation subgroups, the prevalence of BRCA2 germline mutation is similar to the entire population (EGFR 1.79%; ALK 1.74%; KRAS 2.05%; BRAF 2.86%; ERBB2 0.93%; p > 0.05). K2729N is the most common BRCA2 germline mutation (41, 27.7%), followed by C315S (26, 17.6%), V2109I (12, 8.1%), R2108C (11, 7.4%), I2490T (10, 6.8%), T582P (5, 3.4%). About 20% patients with BRCA2 germline mutation carried at least one concomitant mutations of DNA repair genes, including MLH1, MLH3, MSH6, CHEK2, BARD1, BLM, BRCA1, MUTYH, RAD50, RECQL4 and XRCC1. One 56-year-old male LUAS patient, with germline BRCA2 rs80359490 frameshift deletion mutation (p.S1722Yfs*4), received the targeted therapy with PARP inhibitor Olaparib after multi lines therapies. This patient showed a great PR response to Olaparib, with a PFS of at least 6 months. Conclusions: BRCA1/2 germline mutations were rare in Chinese NSCLC patients. Patients with BRCA2 germline mutations might benefit from PARP-inhibitor treatment.
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Sprissler, Ryan, Bryce Perkins, Laurel Johnstone, Hani M. Babiker, Pavani Chalasani, Branden Lau, Michael Hammer, and Daruka Mahadevan. "Rare Tumor-Normal Matched Whole Exome Sequencing Identifies Novel Genomic Pathogenic Germline and Somatic Aberrations." Cancers 12, no. 6 (June 18, 2020): 1618. http://dx.doi.org/10.3390/cancers12061618.
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Whole exome sequencing (WES) of matched tumor-normal pairs in rare tumors has the potential to identify genome-wide mutations and copy number alterations (CNAs). We evaluated 27 rare cancer patients with tumor-normal matching by WES and tumor-only next generation sequencing (NGS) as a comparator. Our goal was to: 1) identify known and novel variants and CNAs in rare cancers with comparison to common cancers; 2) examine differences between germline and somatic variants and how that functionally impacts rare tumors; 3) detect and characterize alleles in biologically relevant genes-pathways that may be of clinical importance but not represented in classical cancer genes. We identified 3343 germline single nucleotide variants (SNVs) and small indel variants—1670 in oncogenes and 1673 in tumor suppressor genes—generating an average of 124 germline variants/case. The number of somatic SNVs and small indels detected in all cases was 523:306 in oncogenes and 217 in tumor suppressor genes. Of the germline variants, six were identified to be pathogenic or likely pathogenic. In the 27 analyzed rare cancer cases, CNAs are variable depending on tumor type, germline pathogenic variants are more common. Cell fate pathway mutations (e.g., Hippo, Notch, Wnt) dominate pathogenesis and double hit (mutation + CNV) represent ~18% cases.
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Brown, Anna L., Christopher N. Hahn, Catherine Carmichael, Ella Wilkins, Milena Babic, Chan-Eng Chong, Xiao-Chun Li, et al. "Expanded Phenotypic and Genetic Heterogeneity in the Clinical Spectrum of FPD-AML: Lymphoid Malignancies and Skin Disorders Are Common Features in Carriers of Germline RUNX1 Mutations." Blood 128, no. 22 (December 2, 2016): 1212. http://dx.doi.org/10.1182/blood.v128.22.1212.1212.
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Abstract Background: This year, germline predisposition to haematological malignancy (HM) debuts in the World Health Organization classification of myeloid neoplasms and acute leukemia (Blood, 2016;127:2391). It has been 17 years since germline mutations in RUNX1 were found to lead to familial platelet disorder (FPD) with predisposition to myelodysplastic syndrome and acute myeloid leukaemia (MDS/AML) (Nat Genet. 1999;23:166). Now, nearly 80 families have been reported with damaging germline mutations or deletions affecting RUNX1 function, associated with FPD, making it an increasingly significant clinical presence. Although thrombocytopenia and platelet dysfunction are present in almost all RUNX1 mutant carriers, we and others have observed that the predisposition to HM varies between family members, with respect to age at diagnosis and the type of malignancy, and in some cases RUNX1 mutation carriers have no apparent HM development over their lifespan. The reasons for this heterogeneity are currently unknown. Aims: We are conducting an international collaborative study examining RUNX1 mutated families. The aim of the research project is to classify the range of phenotypes correlated with RUNX1 mutations comprehensively (including non-malignant phenotypes such as skin disorders) and to determine if the type of RUNX1 mutation and the presence of other germline and acquired mutations in relevant HM genes correlate with the likelihood of HM development, or the type of HM that develops. Across all of our data we aim to analyse clinically relevant information that will be used to inform prognosis and clinical management in germline RUNX1 mutation carriers. Results:From a review of the literature for previously characterised RUNX1 mutant families most mutations are predicted to be loss-of-function, with the combination of frameshift, stopgain, splicing and deletion accounting for the majority of alterations (57, 70%) compared to missense mutations (22, Figure 1). The most common sites of mutation are R201 and R204, affected by both missense and stopgain (10 total), which lie within the nuclear localisation signal at the end of the RUNT domain (Figure 1). We also surveyed in detail 12 RUNX1 pedigrees with both novel and previously described missense, frameshift, stopgain and deletion mutations and found that, while all families developed myeloid malignancies, 6 families also had individuals who developed lymphoid malignancy (most often Acute lymphoblastic leukemia (ALL)) which was heritable in sub-families, and subject to anticipation (e.g see IV-5 and V-5 in Figure 2). Consistent with population genome wide association studies identifying RUNX1 as a susceptibility locus for psoriasis (J Autoimmun. 2015;64:66), we find that skin conditions (psoriasis, eczema) are common, and present in germline RUNX1 carriers in 50% of our families; most commonly observed in families with stopgain and frameshift mutations. Genomic analysis of selected samples confirms that mutation of the other RUNX1 allele is the most commonly acquired mutation in germline RUNX1 mutation carriers developing HM. Alterations of chromosomes 21 and 7 are also common. DNMT3A and PHF6 acquired mutations were the next most frequently observed in tumors and mutations in U2AF1 and ASXL1 in the blood of RUNX1 carriers without HM were observed, suggestive of pre-HM clonal expansion. Finally, in a family with a novel R169I RUNX1 mutation, a rare germline ASXL1 variant (E1102D, 1.0% in ExAC) was found in two RUNX1 carriers who developed early onset AML. This variant is also significantly enriched in an MDS cohort unselected for family history compared to the general population (HR 1.3, p=0.02), as well as ASXL1 N986S (0.1% in ExAC, HR 3.3, p=0.0002) suggesting they operate as germline HM risk modifiers. Interestingly RUNX1 and ASXL1 acquired mutations often co-occur in sporadic MDS/AML and our data suggests this collaboration may also occur at the germline level. Conclusions:Annotation of skin phenotypes co-existent with a family history of haematological malignancy may assist in identifying RUNX1 mutant families. Both acquired and germline mutations in known HM genes may modify germline RUNX1 driven HM penetrance and phenotype. Our data suggest that screening of RUNX1 germline mutation carriers for germline and acquired variants in other HM genes could provide an important tool for defining risk and requires further investigation. Disclosures Owen: Pharmacyclics: Research Funding; Janssen: Honoraria; Roche: Honoraria, Research Funding; Novartis: Honoraria; Gilead: Honoraria, Research Funding; Lundbeck: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Abbvie: Honoraria. Godley:UpToDate: Honoraria; Onconova, Inc.: Research Funding.
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Huelsman, Karen M., Jack B. Basil, Rebecca Sisson, Lindsay R. Lipe, Brett Mahon, and David J. Draper. "Somatic Tumor Profile Analysis in a Patient with Germline PMS2 Mutation and Synchronous Ovarian and Uterine Carcinomas." Journal of Personalized Medicine 11, no. 7 (July 5, 2021): 634. http://dx.doi.org/10.3390/jpm11070634.
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Lynch syndrome patients with synchronous endometrial and ovarian cancer (SEOC) are rare. When these cases occur, they are most often endometrioid histology and early grade. Early-grade tumors are not often sent for somatic tumor profiling. We present a 39 year old SEOC patient with germline PMS2 Lynch syndrome and clinical tumor analysis leading to insight regarding the origin and cause of these tumors, with potential therapy options. PMS2-related SEOC is less common due to lower risks for these cancers associated with germline PMS2 mutation compared to other Lynch genes. While synchronous cancers are not common, they are more likely to occur with Lynch syndrome. Tumor profiling with next-generation sequencing of 648 genes identified sixteen shared somatic actionable and biologically relevant mutations. This case is a rare example of a patient with PMS2 germline Lynch syndrome with shared somatic variants that demonstrate clonality of the two tumors arising from one common site.
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de Smith, Adam J., Geneviève Lavoie, Kyle M. Walsh, Sumeet Aujla, Erica Evans, Helen M. Hansen, Ivan Smirnov, et al. "Germline GAB2 Mutations in Childhood Acute Lymphoblastic Leukemia." Blood 132, Supplement 1 (November 29, 2018): 388. http://dx.doi.org/10.1182/blood-2018-99-119235.
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Abstract Recent studies using next-generation sequencing of selected individuals, such as those with familial leukemia or congenital syndromes, have identified rare and highly penetrant germline mutations that predispose to childhood acute lymphoblastic leukemia (ALL). High hyperdiploidy (HD), the most common cytogenetic subtype of childhood ALL, is enriched in children with RASopathies who develop ALL and, similarly, a high proportion of ALL patients with germline ETV6 or IKZF1 mutations presented with the HD subtype. Here, we aimed to identify novel predisposition genes in a selected group of HD-ALL patients. Targeted sequencing of 538 cancer-relevant genes was carried out using the UCSF500 Cancer Gene Panel in diagnostic bone marrow (i.e. tumor) DNA from 57 HD-ALL patients from the California Childhood Leukemia Study (CCLS). HD-ALL patients were selected based on absence of somatic KRAS or NRAS hotspot mutations detectable by Sanger sequencing, and absence of somatic copy number deletions from multiplex ligation-dependent probe amplification (MLPA) assays. After filtering out likely somatic mutations (mutant allele fraction <0.44), and restricting to variants with low frequency in unselected individuals (allele frequency <0.01% in the Exome Aggregation Consortium, ExAC) and with predicted functional effects (Combined Annotation Dependent Depletion, CADD score ≥20), we identified 151 putative predisposing mutations. Of 41 mutations of interest selected for validation, 37 (90.2%) were confirmed as germline in origin via Sanger sequencing of remission or newborn bloodspot DNA. Rare and predicted functional germline mutations in known (NBN, SH2B3, ETV6, CREBBP, MSH6) or suspected (MLL, ABL1, FLT3, MYH9) ALL predisposition genes were identified in nine out of 57 patients (15.8%). Three additional patients harbored germline mutations in the GRB2-associated binding protein 2 (GAB2), a known binding partner of PTPN11-encoded SHP2 and activator of the ERK/MAPK and PI3K/AKT pathways. Two GAB2 mutations, a missense mutation S592F and frameshift mutation P621fs, were predicted to be highly functional (CADD scores = 34 and 36 respectively) and absent in ExAC. Frequency of rare and damaging GAB2 mutations was significantly higher in our patient set (2.6%) than in ExAC (0.28%, P = 2.70 x 10-6). We replicated this finding in sequencing data from 309 ALL patients in the TARGET (Therapeutically Applicable Research to Generate Effective Treatments) project (0.81% vs. 0.28%, P = 0.015). Patient GAB2 mutations were cloned into HEK293 cells and, following EGF stimulation, we found that the P621fs mutation reduced SHP2 binding and ERK1/2 phosphorylation but increased AKT phosphorylation. This suggested possible Ras-independent leukemogenic effects, supported by a lack of somatic Ras pathway mutations in the three GAB2 mutant patients. Additional functional analyses and sequencing of larger patient cohorts will be required to elucidate the role of germline GAB2 mutations in childhood ALL. Disclosures No relevant conflicts of interest to declare.
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Claes, Kathleen, Eva Machackova, Michel De Vos, Bruce Poppe, Anne De Paepe, and Ludwine Messiaen. "Mutation Analysis of the BRCA1 and BRCA2 Genes in the Belgian Patient Population and Identification of a Belgian Founder Mutation BRCA1 IVS5+3A>G." Disease Markers 15, no. 1-3 (1999): 69–73. http://dx.doi.org/10.1155/1999/241046.
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Since the identification of the BRCA1 and BRCA2 genes, several hundred different germline mutations in both genes have been reported. Recurrent mutations are rare and mainly due to founder effects. As the mutational spectrum of the BRCA1 and BRCA2 genes in the Belgian patient population is largely unknown, we initiated mutation analysis for the complete coding sequence of both genes in Belgian families with multiple breast and/or ovarian cancer patients and in “sporadic” patients with early onset disease. We completed the analysis in 49 families and in 19 “sporadic” female patients with early onset breast and/or ovarian cancer. In 15 families we identified a mutation (12 mutations in BRCA1 and 3 mutations in BRCA2). In 5 apparently unrelated families the same splice site mutation was identified (BRCA1 IVS5+3A>G). Haplotype analysis revealed a common haplotype immediately flanking the mutation in all families suggesting that disease alleles are identical by descent. In none of the 19 sporadic patients was a mutation found.
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Rodrigues, Fernanda Martins, Nadezhda V. Terekhanova, Gad Getz, and Li Ding. "Abstract 754: Pan cancer analysis of germline variants in the CPTAC dataset highlights their significance and functional importance in cancer development." Cancer Research 82, no. 12_Supplement (June 15, 2022): 754. http://dx.doi.org/10.1158/1538-7445.am2022-754.
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Abstract Germline variants play important roles in cancer susceptibility and development, but identification and interpretation of germline variation impacting cancer risk remains a challenge. There has been little research on the impact of germline variants on somatic global/phosphoproteomics landscapes, and even less so for their impact on other tumor characteristics. Here we use cross-cancer genomic, transcriptomic, and global/phosphoproteomics datasets from CPTAC (Clinical Proteomic Tumor Analysis Consortium) to study the global impact of germline variants (common and rare) and the differential impact of germline vs somatic mutations on oncogenic processes, the tumor microenvironment (TME), and treatment responses. We analyze data from 1,093 cases across 10 cancer types (BR, CO, OV, EC, HNSCC, PDAC, LSCC, LUAD, GBM, and ccRCC). We investigate the impact of rare pathogenic variants across cancer types, discerning cancer-gene associations enriched with predisposing variants. We find novel instances of cancer-gene associations not found using TCGA data alone. Loss of heterozygosity (LOH) analyses of germline variants show that BRCA2 may be involved in predisposition not only in BRCA and OV, but also in LUAD. We also see ATM LOH events in ccRCC, CO, and LSCC. Analyses of the effects of germline vs somatic mutations on gene, protein, and phosphoprotein expression revealed significantly different protein expression levels in carriers of pathogenic germline variants vs somatic mutations, notably within core MMR-genes (MSH2, MSH6, PMS2). We examine trans-effects of germline variants on interacting proteins using proteomic/phosphoproteomic data, finding multiple trans-effects of BRCA1 pathogenic variants on the phosphoprotein expression of genes known to interact with BRCA1. Finally, we explore associations of germline and somatic causal events, noting proteomic and mutational signatures indicative of mutational processes taking place in the cell. We see direct relationships between mutations in core gene members of key DNA-damage response pathways (mismatch repair, homologous recombination repair) and the respective signatures associated with those pathways’ deficiencies. Additional analyses include: quantitative trait locus (QTL) analyses to assess the impact of common germline variants on gene (eQTL), protein (pQTL), and phosphoprotein levels (phQTL); analyses of the impact of germline variants on protein signaling during oncogenesis by mapping germline variants to post-translational modification sites); impact of germline variants on the immune landscape and tumor microenvironment (TME); and analyses of paired tumor and Normal Adjacent Tissue (NAT) samples for the discovery of immunogenic germline variants. This study illustrates the broad influence of germline variants on mutational landscapes and their functional impact on cancer. Citation Format: Fernanda Martins Rodrigues, Nadezhda V. Terekhanova, Oncogenic Drivers, Pathways Group, Clinical Proteomic Tumor Analysis Consortium, Gad Getz, Li Ding. Pan cancer analysis of germline variants in the CPTAC dataset highlights their significance and functional importance in cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 754.
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Skoda, Radek C. "Predisposition to Myeloproliferative Neoplasms." Blood 124, no. 21 (December 6, 2014): SCI—33—SCI—33. http://dx.doi.org/10.1182/blood.v124.21.sci-33.sci-33.
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Familial forms of myeloproliferative neoplasms (MPN) and genetic contribution to sporadic cases of MPN have long been recognized. In the majority of cases, familial MPN is inherited as an autosomal dominant trait. The penetrance varies from around 20% to up to 100% in some pedigrees. We can distinguish two types of familial MPN. Type 1 has high penetrance, polyclonal hematopoiesis and hyperproliferation of a single hematopoietic lineage, caused by mutations in a single gene and usually manifesting at birth or early childhood. Examples are mutations in the genes for the erythropoietin receptor, thrombopoietin or its receptor, MPL. The type 2 familial MPNs are characterized by clonal hematopoiesis, low penetrance and manifestation beginning in most cases later in adult life. These type 2 familial MPNs are classical examples of inherited predisposition to a clonal malignant disease, in which acquired somatic mutations in hematopoietic cells are required for disease manifestation. Affected family members typically display the same acquired driver mutations in the genes for JAK2 (JAK2-V617F or JAK2-exon12), MPL (MPL-W515), or calreticulin (CALR) as patients with sporadic MPN. The mutated genes and the mechanism of how these inherited germline mutations predispose to MPN have not yet been elucidated. The search for these germline mutations has been hampered by the low penetrance of MPN manifestation and the rare occurrence of pedigrees that are large enough for genetic studies. Furthermore, the few candidate gene mutations that have been identified to date do not map to one gene locus and the function of the candidate genes does not fall into a common category. Two models of how the germline predisposition interacts with acquired driver mutations can be considered. First, the germline mutation may increase the mutation rate for gene mutations in JAK2, MPL, and CALR. Second, the germline mutation functionally synergizes with mutations in JAK2, MPL, and CALR and promotes disease initiation. The current state of our studies and studies in other laboratories will be discussed. Disclosures Skoda: Novartis: Consultancy; Sanofi: Consultancy.
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Hahn, Christopher N., Milena Babic, Andreas W. Schreiber, Monika M. Kutyna, L. Amilia Wee, Anna L. Brown, Michelle Perugini, et al. "Rare and Common Germline Variants Contribute to Occurrence of Myelodysplastic Syndrome." Blood 126, no. 23 (December 3, 2015): 1644. http://dx.doi.org/10.1182/blood.v126.23.1644.1644.
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Abstract Background: Majority of MDS cases appear to be sporadic in nature, but 10-15% have clear familial basis due to predisposing mutations in genes such as RUNX1, GATA2, CEBPA and DDX41. Contribution of germline variants in sporadic MDS is not studied. This study attempts to address the contribution of germline variants in MDS pathogenesis. Methods: We performed amplicon-based massively parallel sequencing (AmpliSeq custom panel adapted for Illumina HiSeq2500 sequencing) on all coding regions of 29 myeloid genes for 144 MDS samples. After identifying the variants in five genes (TET2, MET, GATA2, ASXL1, NOTCH1), we tested an additional 96 MDS samples including therapy-related myeloid neoplasm (T-MN) using a Sequenom assay. We also analyzed WES data for these variants in 178 AML samples and 758 normal controls and AmpliSeq data for ASXL1 and TET2 variants in 655 CML samples. Results: Collation of all coding variants in the 29 myeloid genes sequenced identified germline variants occurring in primary MDS at frequencies significantly higher than expected when compared to the normal population (ExAC and matched cohort were similar) (Table 1). These variants occurred in 5 genes (TET2, MET, GATA2, ASXL1 and NOTCH1) at increased frequencies of 1.5-16.6 fold. Numerous MDS samples had multiple variants (4 with 4 variants, 4 with 3 variants, 18 with 2 variants) while 70 had 1 variant. The 3 germline MET variants have been previously investigated in solid tumorigenesis and likely generate MET variant proteins that contribute to numerous cancer types including MDS. Interestingly, 7/17 (41%) MDS cases with germline MET variants also had other cancers including pancreatic, gastric and laryngeal cancers. Of the TET2 variants, Y867H and P1723S were concurrent in 5 MDS, 5 AML and 6 CML samples indicative of them being on the same allele (i.e. a haplotype). They were seen at higher than normal frequency in MDS and AML, but were not significantly enriched in CML. We are currently confirming their coexistence on the same allele and assaying for decreased TET2 activity to determine whether one or both variants contribute to the phenotype. Other variants identified in MDS include the rare GATA2 (P161A) variant which is present in 1% of the population and the nearby common GATA2 (A164T) allele (~20%). These were mutually exclusive in our cohort and were seen at 3.9 and 1.5-fold, respectively, above the expected population frequency. We generated the P161A variant using site-directed mutagenesis and assayed for GATA2 transactivation activity in HEK293 cells with a GATA2-responsive LYL1 promoter-Luciferase construct (Figure 1). We also included empty vector (EV), wildtype (WT) GATA2 and T354M which is the most common highly penetrant autosomal dominant mutation leading to familial MDS/AML. As expected, T354M displayed a marked decrease in transactivation ability when compared to WT. The P161A variant similarly displayed loss-of-function in this assay, but not to the same magnitude as T354M. This is consistent with the hypothesis that reduced GATA2 function predisposes to myeloid malignancy where decreasing GATA2 activity correlates with increasing risk of developing malignancy. In our study 10/36 (28%) cases harboring these variants were T-MN cases. Apart from MET (E168D) (11.4-fold), the 2 rare variants with highest frequency in MDS versus controls were ASXL1 (N986S) (16.6-fold) and NOTCH1 (R912W) (6.5-fold). ASXL1 is an epigenetic regulator often mutated in hematopoietic malignancy and aberrant NOTCH1 function has been associated with myeloid and lymphoid malignancies. Conclusions: We have identified common and rare germline variants in genes involved in myeloid malignancy that may contribute to MDS pathogenesis. It remains to be seen whether they contribute to initiation, maintenance and/or progression of MDS and other hematopoietic malignancies. This is the first study reporting higher frequency of germline variants in sporadic MDS cases. Table 1. Frequency of germline variants in MDS, AML and CML in comparison to ExAC. Table 1. Frequency of germline variants in MDS, AML and CML in comparison to ExAC. Disclosures Hiwase: Celgene Corporation: Research Funding.
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Bornhorst, Miriam, Liana Nobre, Michal Zapotocky, Hayk Barseghyan, Jeremy Goecks, Daniel Boue, Uri Tabori, et al. "PATH-14. GENETIC SUSCEPTIBILITY AND OUTCOMES OF PEDIATRIC, ADOLESCENT AND YOUNG ADULT IDH-MUTANT ASTROCYTOMAS." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii427. http://dx.doi.org/10.1093/neuonc/noaa222.649.
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Abstract INTRODUCTION Previously thought to be rare, recent case series have shown that IDH mutations in young patients are more common than previously described. In this study, we analyzed IDH-mutant tumors to determine clinical significance of these mutations in children, adolescents and young adults. METHODS Through this multi-institution study (10 institutions), we collected 64 IDH1/2-mutant infiltrating astrocytoma specimens from 58 patients aged 4–26 (M:F, 0.4:0.6). Specimens included 46 low-grade (LGG) and 18 high-grade (HGG) astrocytomas. Tumor sequencing data (n=45), germline sequencing data (n=37) and outcome data (n=40) was analyzed. RESULTS Similar to adults, most sequenced tumors had a co-mutation in the TP53 gene, while ATRX mutations were less common and primarily seen in HGGs. Approximately 60% (n=21) of patients with germline data available had a mutation in a cancer predisposition gene. Mismatch repair (MMR) mutations were most common (n=12; MSH6 n=9), followed by TP53mutations (n=7). All patients with MMR gene mutations had HGGs and poor progression free (PFS=10% at 2 years, mean TTP=9 months) and overall (OS <30% at 2 years) survival. Despite an OS of 90% at 5 years, many LGG patients had tumor progression/recurrence requiring additional treatment (PFS= 80% at 2 yrs, 40% at 5 yrs, mean TTP=3.5 years). Four LGG tumors (2 with TP53+ATRXloss, 2 with TP53 loss+1p19q co-deletion) underwent malignant transformation. CONCLUSION IDH-mutant tumors in pediatric patients are strongly associated with cancer predisposition and increased risk for progression/recurrence or malignant transformation. Routine screening for IDH1/2 mutations in children with grade 2–4 astrocytomas could greatly impact patient management.
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Dishion, Evan, Clayton Korson, and Darren Groh. "RARE-41. GLIOBLASTOMA MULTIFORME AND OTHER CNS TUMORS IN HEREDITARY MISMATCH REPAIR DEFICIENCIES." Neuro-Oncology 21, Supplement_6 (November 2019): vi230. http://dx.doi.org/10.1093/neuonc/noz175.964.
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Abstract BACKGROUND Lynch syndrome (LS) and constitutional mismatch repair deficiency syndrome (CMMRD) are caused by germline mutations in mismatch repair (MMR) genes, namely MLH1, MSH2, MSH6, and PMS2. LS patients have an inherited mono-allelic MMR defect, whereas CMMRD patients have a bi-allelic defect. MMR is critical to maintaining genomic integrity during DNA replication and these germline defects are known to produce microsatellite instability (MSI). Both LS and CMMRD have reported cases of increased primary brain cancer, namely glioblastoma multiforme (GBM). Given the shared pathophysiology of these syndromes, the large number of cases and registry studies published, and recent treatments of CNS tumors in CMMRD, a literature review has been conducted. OBJECTIVES: Review the pathophysiology of germline MMR deficiency and how it relates to brain tumor formation. Review the risk of developing primary CNS tumors with various MMR defects. Review the current management of CNS tumors in LS and CMMRD. METHODS Literature review of the most recent understanding of pathophysiology, all literature on CNS tumors in LS and CMMRD, and the current management of GBM including recent literature on CMMRD. RESULTS The lifetime risk of developing a primary malignant brain tumor or other CNS tumor in the United States has been calculated at 0.62%. Based on registry data, current estimates of the lifetime risk of developing a primary CNS tumor in LS is between 1–8.7%. Of the 146 genetically confirmed cases of CMMRD, 58 cases of high-grade gliomas were identified (including GBM). Most patients with CMMRD carry homozygous germline mutations in PMS2 (approximately 60%). Although primary CNS tumors appears to be a less common extra-colonic manifestation in LS, it is relatively common amongst CMMRD patients. Acknowledgement: Henry Lynch
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Stieglitz, Elliot, Y. Lucy Liu, Peter D. Emanuel, Robert P. Castleberry, Todd Michael Cooper, Kevin Shannon, and Mignon L. Loh. "Mutations In GATA2 Are Rare In Juvenile Myelomonocytic Leukemia." Blood 122, no. 21 (November 15, 2013): 1526. http://dx.doi.org/10.1182/blood.v122.21.1526.1526.
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Abstract Germline mutations in GATA2, a gene that encodes for transcription factors involved in hematopoiesis and vascular development, have recently been described in MonoMAC syndrome, Emberger syndrome and in select cases of mild chronic neutropenia. These disorders are unified by their predisposition to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Patients with MonoMAC syndrome have also been noted to display monosomy 7 in their bone marrows in up to 50% of cases. Overexpression of GATA2 due to somatic mutations in cases of de novo pediatric AML, has also been shown to be a negative predictor of outcome. Juvenile myelomonocytic leukemia is a rare childhood malignancy with overlapping features of MDS and myeloproliferative neoplasm (MPN) that can transform to AML and is characterized by hyperactive RAS signaling. Mutations in NF1, NRAS, KRAS, PTPN11, and CBL are found in 85-90% of newly diagnosed patients, and monosomy 7 is the most common recurrent karyotypic abnormality seen in JMML. We therefore hypothesized that mutations in GATA2 may play a role in the development of JMML. Samples from 57 patients with JMML were screened for GATA2 mutations. Patient samples and clinical data were collected from the Children's Oncology Group (COG) trial AAML0122. DNA was extracted as per previous protocols from peripheral blood or bone marrow and whole genome amplified using Qiagen REPLI-g kit according to manufacturer specifications. We performed bidirectional Sanger sequencing (Beckman Coulter Genomics) of the entire coding region of GATA2 (NM_001145661.1) and aligned the sequences using CLC Workbench software (CLC Bio, Aarhus, Denmark). Only missense, splice site or nonsense mutations were evaluated using SIFT (Sorting Tolerant From Intolerant) to predict the impact on the structure and function of identified mutations on the protein. Patient J384 was found to have a nonsense point mutation at c.988C>T (R330X) in the N-terminal region of the zinc finger portion of the protein (Figure 1a). This hotspot mutation has been reported in several patients with mild chronic neutropenia who displayed a predisposition to developing MDS and AML. The patient was also found to have a missense point mutation at c.962T>G (L321R) predicted to be damaging by SIFT. Subcloning of the gene using a TA cloning kit with pCR 2.1 vector (Invitrogen), followed by direct sequencing of individual colony picks, revealed that the two sequence variants only occurred in a trans configuration. Out of 40 amplicons sequenced, 20 were found to have the c.988C>T transition, 16 were found to be have the c.962T>G variant, and four were found to be wild type. We therefore hypothesize that the c.988C>T was inherited as a germline event and that c.962T>G was somatically acquired in the majority of the remaining wild type alleles. No other point mutations or insertions/deletions were discovered in this cohort.Figure 1Identification of 2 distinct GATA2 mutations in patient J384.Figure 1. Identification of 2 distinct GATA2 mutations in patient J384. This patient was previously identified to have a KRAS G12D mutation (c.35G>A) as well as monosomy 7. This patient died prior to undergoing transplant within months of diagnosis. While the patient technically met criteria for the diagnosis of JMML, it should be noted there were several atypical features, including older age at diagnosis (4 years and 10 months), and absence of hypersensitivity in myeloid progenitor cells to the cytokine granulocyte–macrophage colony stimulating factor (GM-CSF) in colony assay. This raises the possibility that patient J384 actually had MonoMAC syndrome with MDS and not JMML. This represents the first description of a GATA2 mutation in a patient suspected of having JMML. To our knowledge, this is the first report of a biallelic mutation in GATA2, combining a germline mutation with somatic acquisition. In addition, MonoMAC syndrome has not been reported to be associated with KRAS mutations to date. GATA2 mutations should therefore be considered in patients with atypical features of MDS or JMML. Panel (a) Bidirectional sequencing of patient sample J384 revealed two distinct sequence variants in both the forward (shown here) and reverse strands. Panel (b) Sequencing of 40 individual colony picks revealed that each sequence variant occurred in a trans configuration (CP 9 and CP13 are shown here as examples). In addition, 10% of colony picks (i.e. CP 32) revealed a wild type sequence, indicating that at least one of the two variants was a somatic event. Disclosures: No relevant conflicts of interest to declare.
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de Smith, Adam J., Kyle M. Walsh, Ivan Smirnov, Sumeet Aujla, Erica Sanders, Hansen M. Helen, Catherine Metayer, and Joseph L. Wiemels. "Somatic and Germline Mutational Heterogeneity in High Hyperdiploid Acute Lymphoblastic Leukemia." Blood 128, no. 22 (December 2, 2016): 1727. http://dx.doi.org/10.1182/blood.v128.22.1727.1727.
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Abstract High hyperdiploidy (HD), the most common cytogenetic subtype of acute lymphoblastic leukemia (ALL), is characterized by a nonrandom gain of chromosomes and is thought to arise from a single abnormal mitosis. However, the causes of this leukemia-initiating event remain unknown. A recognized enrichment of HD-ALL among children with RASopathies and with germline ETV6 mutations suggests that germline predisposition underlies a component of HD-ALL risk, in addition to the increased risk of the HD subtype with ALL-associated heritable risk variants in PIP4K2A, ARID5B, and CEBPE. Though cure rates of HD-ALL are high, the significant treatment-related morbidities and mortality warrant more etiologic investigations which may reveal molecularly-targeted therapies for this disease. We carried out deep-sequencing of 538 cancer-related genes using the UCSF500 Cancer Gene Panel in 57 HD-ALL tumors from California Childhood Leukemia Study patients. Selected patients lacked overt KRAS and NRAS hotspot mutations (assessed by Sanger sequencing) and common ALL deletions (assessed by MLPA), to enrich for discovery of novel driver genes. A Combined Annotation Dependent Depletion (CADD) Phred score ≥20 was used to filter predicted damaging mutations. To remove polymorphisms, we retained only mutations with allele frequency <0.01% in the Exome Aggregation Consortium (ExAC). We adjusted the mutant allele fraction (MAF) of each mutation in relation to chromosome copy-number, as determined using the CNVkit tool. Sanger sequencing of remission DNA was used to validate a subset of predicted germline mutations (adjusted MAF≥0.45) of interest, including in known ALL predisposition genes. Novel damaging somatic mutations were discovered in epigenetic regulatory genes, including DOT1L (n=4), with 33% of patients harboring mutations in this pathway. Somatic mutations in the receptor tyrosine kinase (RTK)/Ras/MAPK signaling pathway were found in two thirds of patients, including mutations in ROS1, which mediates phosphorylation of the PTPN11-encoded protein SHP2. An extraordinary level of tumor heterogeneity was detected, with microclonal (mutant allele fraction <10%) hotspot mutations in KRAS, NRAS, FLT3 or PTPN11 identified in 31/57 (54.4%) patients. Multiple microclonal mutations at KRAS and NRAS codons 12 and 13 significantly co-occurred within tumor samples (P=4.8x10-4), suggesting ongoing formation of, and selection for, Ras mutation. Moreover, 7 patients had multiple microclonal mutations at the same Ras hotspot locus, in adjacent codon 12/13 nucleotides or in adjacent codons. The adjacent mutations occurred on different sequencing reads in all 7 patients (P=0.016), indicating they were part of distinct tumor subclones. We also detected an unexpectedly high frequency of putatively causal germline mutations, which were validated in remission DNA samples by Sanger sequencing. At least 25% of HD-ALL patients carried one or more rare (<0.01% allele frequency in ExAC) and predicted-damaging germline mutations in known ALL predisposition genes, DNA repair genes, or within known hotspot mutation loci that had previously been reported mutated only in tumor genomes. Future work is required to investigate whether tumor microheterogeneity should impact therapeutic regimens and to elucidate the biologic function of epigenetic dysregulation in development of HD-ALL. Whole-exome sequencing of more patients and functional analysis of novel mutations are required to understand the contribution of germline predisposition to HD-ALL etiology, which may be much larger than previously realized. Disclosures No relevant conflicts of interest to declare.
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Wagner, SD, V. Martinelli, and L. Luzzatto. "Similar patterns of V kappa gene usage but different degrees of somatic mutation in hairy cell leukemia, prolymphocytic leukemia, Waldenstrom's macroglobulinemia, and myeloma." Blood 83, no. 12 (June 15, 1994): 3647–53. http://dx.doi.org/10.1182/blood.v83.12.3647.3647.
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Abstract To compare V kappa gene usage and the amount of somatic mutation in rearranged Ig genes from patients with lymphoproliferative disorders, we have polymerase chain reaction-amplified and sequenced a total of 26 V kappa genes from a total of 55 cases. Six sequences were obtained both from six cases of prolymphocytic leukemia (PLL) and from nine cases of hairy cell leukemia (HCL). Seven sequences were obtained both from 11 cases of Waldenstrom's macroglobulinemia (WM) and 29 cases of multiple myeloma (MM). Eleven different germline genes have been used in this series, indicating a wide but nonrandom usage of germline Ig gene rearrangements in these disorders. Comparison of the nucleotide sequences of V kappa genes obtained from B-cell malignancies with germline V kappa genes shows that somatic mutation is rare in PLL and HCL and common in WM and MM. Analysis of the pattern of mutations suggests that WM and MM are derived from B cells that have been selected by antigen at a relatively late stage of differentiation.
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Wagner, SD, V. Martinelli, and L. Luzzatto. "Similar patterns of V kappa gene usage but different degrees of somatic mutation in hairy cell leukemia, prolymphocytic leukemia, Waldenstrom's macroglobulinemia, and myeloma." Blood 83, no. 12 (June 15, 1994): 3647–53. http://dx.doi.org/10.1182/blood.v83.12.3647.bloodjournal83123647.
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To compare V kappa gene usage and the amount of somatic mutation in rearranged Ig genes from patients with lymphoproliferative disorders, we have polymerase chain reaction-amplified and sequenced a total of 26 V kappa genes from a total of 55 cases. Six sequences were obtained both from six cases of prolymphocytic leukemia (PLL) and from nine cases of hairy cell leukemia (HCL). Seven sequences were obtained both from 11 cases of Waldenstrom's macroglobulinemia (WM) and 29 cases of multiple myeloma (MM). Eleven different germline genes have been used in this series, indicating a wide but nonrandom usage of germline Ig gene rearrangements in these disorders. Comparison of the nucleotide sequences of V kappa genes obtained from B-cell malignancies with germline V kappa genes shows that somatic mutation is rare in PLL and HCL and common in WM and MM. Analysis of the pattern of mutations suggests that WM and MM are derived from B cells that have been selected by antigen at a relatively late stage of differentiation.
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Oczko-Wojciechowska, Malgorzata, Agnieszka Czarniecka, Tomasz Gawlik, Barbara Jarzab, and Jolanta Krajewska. "Current status of the prognostic molecular markers in medullary thyroid carcinoma." Endocrine Connections 9, no. 12 (December 2020): R251—R263. http://dx.doi.org/10.1530/ec-20-0374.
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Medullary thyroid cancer (MTC) is a rare thyroid malignancy, which arises from parafollicular C-cells. It occurs in the hereditary or sporadic form. Hereditary type is a consequence of activation of the RET proto-oncogene by germline mutations, whereas about 80% of sporadic MTC tumors harbor somatic, mainly RET or rarely RAS mutations. According to the current ATA guidelines, a postoperative MTC risk stratification and long-term follow-up are mainly based on histopathological data, including tumor stage, the presence of lymph node and/or distant metastases (TNM classification), and serum concentration of two biomarkers: calcitonin (Ctn) and carcinoembryonic antigen (CEA). The type of RET germline mutation also correlates with MTC clinical characteristics. The most common and the best known RET mutation in sporadic MTC, localized at codon 918, is related to a more aggressive MTC course and poorer survival. However, even if histopathological or clinical features allow to predict a long-term prognosis, they are not sufficient to select the patients showing aggressive MTC courses requiring immediate treatment or those, who are refractory to different therapeutic methods. Besides the RET gene mutations, there are currently no other reliable molecular prognostic markers. This review summarizes the present data of genomic investigation on molecular prognostic factors in medullary thyroid cancer.
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Kongkiatkamon, Sunisa, Samuel Li, Tatiana Dombrovski, Laila Terkawi, Cassandra M. Kerr, Vera Adema, Yasunobu Nagata, et al. "Rare Germline Alterations of Myeloperoxidase Predispose to Myeloid Neoplasms and Are Associated with Increased Circulating Burden of Microbial DNA." Blood 136, Supplement 1 (November 5, 2020): 2–3. http://dx.doi.org/10.1182/blood-2020-139972.
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Germline alterations causing inherited myeloid neoplasia (MN) have become prominent in the 2016 WHO classification. Increasing evidence reveals that many patients with MN (MDS and AML) may indeed harbor unsuspected predisposing or direct driver germline alterations. Penetrance of such alterations may be variable and family history unreliable or absent. Our previous screening of a selection of genes known to be involved in the pathogenesis of human cancers directly or indirectly according to the difference in the allelic burden in 690 MN patients (Li, S.T, Leukemia, 2020) we identified the myeloperoxidase (MPO) gene as having the highest burden of pathogenic alterations. MPO (17q22-23) encodes a heme-containing enzyme exclusively expressed in myeloid cells. MPO is known for its role in host defense against common microbial infections. In the presence of H2O2, MPO catalyzes the formation of hypohalous acids which are potent oxidants and strong bactericides. Many alterations in MPO have been found in hereditary MPO deficiency, an autosomal recessive syndrome with variable clinical penetrance. MPO deficiency syndrome is characterized by increased susceptibility to infections. To date, formal cancer association has not been established. In particular due to relatively mild phenotype, hereditary deficiency may remain unrecognized. Inspired by results of an initial screen we investigated MPO mutations in 3262 patients with various bone marrow failure syndromes (AA/PNH, 213) and MN (AML, 1655; MDS, 1133; MDS/MPN, 161; MPN, 100). In a subset of patients (20%), paired normal and tumor samples were sequenced in order to confirm germline origin. Germline MPO mutations were identified in 105 cases with 52% of them in AML. The most common recurrent mutation was c.2031-2A>C (42%; 44/105) (3' splice site of intron11) followed by I642L/F 15% (16/105), R569W 14 % (15/105), M519fs 13% (14/105), R460Q 7% (7/105), Y173C 5% (5/105), and R480H 2% (2/105). None of the variants were biallelic. The expected frequency of overall MPO variants in our cohort was higher than gnomAD (0.26% vs. 0.18%; P= .15×10-3) with odds ratio of 1.4. Notably, MPO mutations were significantly enriched in patients with age < 60 (2.2%; odds ratio =12.1, 95%CI=9.3-17.3; P<.0001). Further clinical characterization revealed that the frequencies of MPO mutations were also higher among different disease types than in controls (0.26%, 0.30%, 1.18% for AML, MDS, AA/PNH, P=.008, .001, <.001). Of interest, only the pathogenic variants that had been reported in MPO deficiency syndrome (c.2031-2A>C, R569W, M519fs, Y173C) contributed to this significant enrichment. Co-occurring lesions of germline MPO mutants (MPOMT) were then investigated: DNMT3A, SF3B1, TP53, NRAS were commonly observed in MPOMT compared to MPO WT-MN (20 vs. 14%, 17 vs. 13%, 16 vs. 8%, and 12 vs. 7%). Normal karyotype was found in 47% of carriers without enrichment for complex, -7/del(7q), del(5q), del(20q) or +8 karyotypes compared to WT. We compared RNA expression patterns between patients with pathogenic MPO mutations and those WT for MPO. Examination of genes significantly overexpressed in MPOMT showed strong enrichment in pseudoperoxidases hemoproteins involved in oxygen transport-globin (P=10-3) and heme biosynthesis (P=.012) (Fig.1C). The overexpression of hemoglobin/myoglobin genes in MPOMT suggests an excessive compensatory process due to the lack of true peroxidase activity. The fact that MPO has microbicidal activity led us to investigate the consequences of MPO mutations. Using shotgun whole-microbiome sequencing of circulating DNA, we examined the overall bacterial load in each patient. We found that MPO pathogenic mutation carriers had significantly higher bacterial burden than non-carriers (Fig.1D). The high bacterial burden of MPO mutants possibly promoted chronic inflammation, known to correlate with cancer pathogenesis. Indeed, we found that the presence of pathogenic MPO mutations was correlated with decreased survival in AML (P = 1.5 x 10-5). In sum, this is the first cohort showing germline MPO variants as predisposing alterations in MN. MPO variants might cause partial or total MPO deficiency resulting in chronic inflammatory responses by excessive compensation of immunity against invading microbes. This chronic inflammation stages can increase proliferation of HSC or myeloid progenitors and give rise to DNA replication associated mutations. Disclosures Maciejewski: Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria.
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Woodward, Emma R., and Eamonn R. Maher. "Von Hippel-Lindau disease and endocrine tumour susceptibility." Endocrine-Related Cancer 13, no. 2 (June 2006): 415–25. http://dx.doi.org/10.1677/erc.1.00683.
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Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome caused by mutations in the VHL tumour suppressor gene. VHL disease is characterised by marked phenotypic variability and the most common tumours are haemangioblastomas of the retina and central nervous system and clear cell renal cell carcinoma. However, endocrine tumours, most commonly phaeochromocytoma and non-secretory pancreatic islet cell cancers, demonstrate marked interfamilial variations in frequency and are significant causes of morbidity and, sometimes, mortality. Genotype–phenotype correlations have revealed that certain missense mutations are associated with a high risk of phaeochromocytoma but total loss of function mutations are associated with a low risk. Furthermore, rare mutations may predispose to a phaeochromocytoma-only phenotype. Germline VHL mutations may be detected in 5–11% of all phaeochromocytoma cases and mutation analysis of VHL and other phaeochromocytoma susceptibility genes (SDHB, SDHD and RET) should be performed in all cases of familial, multiple or early onset phaeochromocytomas, and considered in other cases. The VHL gene product has a key role in regulating the stability of hypoxia-inducible factors (HIF-1 and HIF-2) such that inactivation of VHL leads to up-regulation of HIF-1 and HIF-2 protein expression and activation of hypoxic gene response pathways. Germline SDHB and SDHD mutations also lead to increased expression of HIF target genes, but it appears that phaeochromocytoma susceptibility in VHL disease cannot be attributed to HIF activation alone. Recently, it has been suggested that an HIF-independent failure of developmental apoptosis is a common feature of all inherited phaeochromocytoma susceptibility syndromes.
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Douglas, Suvi, Atte Lahtinen, Jessica Koski, Lilli Leimi, Mikko A. Keränen, Kimmo Porkka, Caroline A. Heckman, Kirsi Jahnukainen, Outi Kilpivaara, and Ulla Wartiovaara-Kautto. "Germline Gene Aberrations Are Common in High-Risk Adult and Pediatric Acute Lymphoblastic Leukemia Patients." Blood 134, Supplement_1 (November 13, 2019): 1472. http://dx.doi.org/10.1182/blood-2019-126657.
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Personalized medicine involves a comprehensive analysis of factors affecting a disease. Family history is an important but not a definitive indicator of inherited predisposition to malignancy and thus studying the germline gene aberrations alongside somatic variants is warranted. The significance of germline predisposition has been increasingly recognized in acute myeloid leukemia and is noted in the latest WHO classification.1,2,3Despite the recent progress in acute lymphoblastic leukemia (ALL) therapies, many adult patients with ALL still do poorly and there is a need for new biomarkers and therapy targets. The aim of our study was to identify and determine the frequency of germline mutations in known ALL genes, to discover new genes associated with ALL predisposition, and to compare the germline genetic background and respective consequences of pediatric and adult high-risk ALL. We examined exome sequencing data from biobanked samples of adult (50) and pediatric (68) patients with high-risk ALL (Finnish Hematological Registry and Biobank - FHRB, and clinical repositories). First, a candidate-gene analysis consisted of 92 genes previously associated with germline predisposition to ALL or syndromes predisposing to ALL. Variants with minor allele frequency of <0.01 in the Genome Aggregation Database were considered. Missense variants were considered significant if ≥2/3 algorithms (CADD, DANN, Revel) classified it as pathogenic. We also reviewed literature, public databases and the American College of Medical Genetics classification (ACMG) in filtering the variants. Clinical characteristics of the patients were retrieved from hospital records and the Finnish Hematological Registry. Second, an unbiased approach was applied to find novel genes predisposing to ALL by checking pathogenic variants in the same gene in at least two (adult/pediatric) patients and filtering by gene ontologies DNA repair, cell cycle, and lymphocyte differentiation; and by COSMIC cancer census genes. In both analyses, only statistically significantly more common variants in our series compared to normal population were included. We also conducted a mutational signature analysis on the samples. Our analysis (Table 1) demonstrates that 8% of adult and 10% pediatric study patients carried a pathogenic or likely pathogenic mutation in their germline in known ALL predisposing genes. All these mutations were at least 30-fold more frequent in our study series compared with allele frequencies in the normal population (p<0.05). Four pediatric patients were identified to suffer from undiagnosed syndromes, which predispose to ALL (Li-Fraumeni and Noonan syndromes). We also found recurring aberrations in new genes with biological relevance to ALL, such as MUTYH and IL21R, potentially associating with ALL predisposition. Final results of the mutational signature analyses are pending. In conclusion, our results emphasize that germline predisposition is not rare among high-risk ALL patients. In addition to pediatric ALL patients, we show contributing germline variants also in adult patients. At least 20% of the adult ALL patients are transplanted and a potential germline basis of the disease should be considered when choosing the donor. Our analysis also reveals new information on the biology of high-risk ALL and may contribute to the future studies seeking for therapy options in this challenging patient category. Despite the anxiety that acknowledging inheritable factors may cause in patients, families, and caretakers, we encourage clinicians to integrate carefully interpreted germline data into patient care. References 1. Wartiovaara-Kautto U et al. Germline alterations in a consecutive series of acute myeloid leukemia. Leukemia. 2018. 2. Arber DA et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016. 3. Tawana K et al. Universal genetic testing for inherited susceptibility in children and adults with myelodysplastic syndrome and acute myeloid leukemia : are we there yet? Leukemia. 2018. Disclosures Porkka: Daiichi Sankyo: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Heckman:Celgene: Research Funding; Novartis: Research Funding; Oncopeptides: Research Funding; Orion Pharma: Research Funding.
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Sorscher, Steven, and Shakti Ramkissoon. "Next-Generation Sequencing in Order to Better Characterize a BRCA Variant of Uncertain Significance." Case Reports in Oncology 10, no. 2 (July 11, 2017): 634–37. http://dx.doi.org/10.1159/000478005.
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BRCA germline mutations are the most common predisposing factor in familial breast-ovarian cancer syndrome families. However, many screened patients are identified as harboring BRCA variants of uncertain significance (VUS), rather than carrying deleterious germline mutations [Calo et al.: Cancers 2010; 2:1644–1660]. While such VUSs are typically reclassified as benign polymorphisms, this may occur years after the VUS is first identified [Murray et al.: Genet Med 2011; 13; 998–1005]. Loss of heterozygosity (LOH) of BRCA is nearly always the gatekeeper event in inherited BRCA-related breast cancer and LOH of BRCA is rare in sporadic cancers [Osorio et al.: Int J Cancer 2002; 99:305–309]. Here, we describe a patient identified as carrying a germline BRCA VUS. Tumor next-generation sequencing (NGS) demonstrated a very high mutation allelic frequency for that BRCA VUS, consistent with LOH. This case illustrates that since BRCA LOH is the typical mechanism of transformation in inherited BRCA-related breast cancers, NGS might be used to suggest that the BRCA VUS is actually cancer predisposing in a particular family. As a result, this may help patients make more informed decisions regarding screening and prophylactic therapy, long before official reclassification of the VUS occurs.
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Hong, Lih En, Deepak Singhal, Amilia Wee, Rakchha Chhetri, Mihir D. Wechalekar, Susanna Proudman, and Devendra K. Hiwase. "The Mutation Profile of Myelodysplastic Syndrome Associated with Auto-Immune Rheumatological Disorders." Blood 132, Supplement 1 (November 29, 2018): 3081. http://dx.doi.org/10.1182/blood-2018-99-119965.
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Abstract Introduction: A subset of patients with MDS and related myeloid disorders present with concomitant autoimmune rheumatological diseases (AIRD); however the prevalence ranges from 10-48% based on limited literature. Further, use of immunosuppressive agents in AIRD patients could confound the secondary diagnosis of MDS and in some cases cause it (therapy-related myeloid neoplasm; t-MN). The prevalence of cytopenia in AIRD patients is unknown and the genetic characteristics of MDS patients with concomitant AIRD have not been described. Hence, we interrogated two large multi-institutional databases -Royal Adelaide Hospital Rheumatology Database (RAH-RD) and South-Australian MDS (SA-MDS) registry in this study. Methods: Demographic, clinical, laboratory and treatment data of 2663 AIRD and 1157 MDS patients were analysed. In AIRD patients (autoimmune inflammatory arthritis, spondyloarthritis, vasculitis and connective tissue diseases), cytopenia (persisting >6 months) were defined as follows: hemoglobin <100g/dL, absolute neutrophil <1800/mm3 and platelet <100,000/mm3. Targeted massively parallel sequencing of a custom panel of 43 myeloid neoplasms associated genes and 20 Fanconi (FA) DNA repair pathway genes (all coding regions) was performed on diagnosis bone marrow samples (n=237). An in-house well established filtering pipeline was used for identification of somatic mutations. Matched germline material was available for 62/194 (32%) patients. Only variants with Genome Aggregation Database minor allele frequency of ≤0.01% and variant allele frequency of ≥35% were selected for further analysis of germline variants. Results: During follow up of 2663 AIRD patients, 36 (1.3%) patients satisfied the criteria for at least one cytopenia. Anemia (19/36, 53%) was most common followed by neutropenia (8/36, 22%), thrombocytopenia (4/36, 11%) and bi-cytopenia (5/36, 14%). Twenty-two patients had bone marrow examination which was non-diagnostic in 16 patients, while 7/2663 (0.3%) patients were diagnosed with MDS. Importantly, 5 patients with MDS and 11 patients with cytopenia did not receive any cytotoxic agents. In the MDS database, 69(5.4%) were diagnosed with AIRD, with rheumatoid arthritis (n=20, 29%) being the most common AIRD. Among these 69 patients, 24 (34.8%) had low risk MDS and 15 (21.7%) had higher risk MDS. The remaining 30 patients had t-MN (n=19, 27.5%), MDS/MPN (n=8, 11.6%) and AML (n=3, 4.3%). Overall, in a combined population of 2663 RAH-RD and 1157 SA-MDS, 76(2%) had concomitant MDS and AIRD. Genetic profile of patients with MDS and AIRD: The cytogenetic and mutational profile of MDS patients with (n=20) or without (n=217) AIRD were compared. No significant difference was seen in the cytogenetic profile (normal, complex or monosomal karyotype, chr. 5 or 7 abnormalities) between the two groups but in mutational analysis, 56 mutations were seen in 20 MDS patients with AIRD (Fig1). In these patients, mutations in epigenetic pathways were most common (23/56, 41%) followed by transcription pathway (10/56, 18%). Splicing mutations were seen in 5 patients, with SRSF2 mutations being more common than SF3B1. Mutations in TP53 were present in 4 (24%) patients; 3/4 patients developed MDS following therapy for AIRD (t-MDS). IDH1 mutations were found in significantly higher frequency in MDS patients with AIRD compared to MDS without AIRD (30% vs 3%, p=0.04). There was no significant difference in the frequency of other mutations or overall mutation frequency between the two groups. Interestingly, 2 (10%) patients with MDS and AIRD also had rare, deleterious germline mutations in FA pathway genes (BRCA2 V2601M and L2512F) which could suggest either genetic predisposition to both these conditions or compromised DNA repair capability increasing susceptibility to t-MN. Conclusions: In a large multi-institutional cohort of autoimmune rheumatological disorders, 1.3% patients developed persistent cytopenia with 0.3% diagnosed with MDS. This is significantly higher than incidence of MDS in the general population (30-50/100,000). Similarly, 5% MDS patients had AIRD. The mutation profile of MDS patients with AIRD shows higher frequency of IDH1 and SRSF2 mutations. A small proportion of cases also had deleterious rare germline mutations in the DNA repair pathway. Our findings warrant further study and have potential implications for selection of immunosupressive agents for AIRD. Disclosures Hiwase: Novartis: Research Funding; Celgene: Research Funding.
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O'Sullivan, Maureen J., Amanda McCabe, Peter Gillett, Iain D. Penman, Gordon A. MacKinlay, and on Pritchard. "Multiple Gastric Stromal Tumors in a Child without Syndromic Association Lacks Common KIT or PDGFRα Mutations." Pediatric and Developmental Pathology 8, no. 6 (November 2005): 685–89. http://dx.doi.org/10.1007/s10024-005-0083-y.
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A diagnosis of multiple gastric stromal tumors that were nonmetastatic at presentation was made in an 11-year-old girl who presented with hematemesis. Gastrointestinal stromal tumor (GIST) is a rare diagnosis in childhood and reported multiple lesions are generally seen in the context of familial disease, occasionally with syndromic associations. Although there are no reports of genetic mutation in cases of pediatric GIST, very many cases of multiple GISTs investigated on a molecular level have shown germline KIT or platelet-derived growth factor receptor-α mutation; these were familial cases. Despite the negative family history in our patient, the multiplicity of lesions in such a young patient raised concern for a genetic predisposition and prompted extensive molecular workup. Repeat evaluation of distinct aliquots of tumor tissue by polymerase chain amplification followed by sequence analysis of selected coding sequences of KIT and platelet-derived growth factor receptor-α previously shown to harbor mutations in GIST, yielded no evidence of even a somatic mutation. This clinically unique case is discussed in the context of a literature review.
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Druley, Todd E., Mark Valentine, Nicholas Sanchez, and Julie A. Ross. "Matched Exome Sequencing in Mothers and Infants with MLL-Negative Acute Leukemia." Blood 120, no. 21 (November 16, 2012): 536. http://dx.doi.org/10.1182/blood.v120.21.536.536.
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Abstract Abstract 536 Introduction: Infant leukemia (IL) is an extremely rare, sporadic, but often fatal, form of cancer that is defined as leukemia occurring within the first year of life. Unlike leukemia in older children where survival rates for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are approximately 70% and 85%, respectively, infants have a survival rate of ∼50%. Unfortunately, despite years of research and clinical trials, overall survival for IL hasn't improved substantially since the advent of hematopoietic stem cell transplantation, and those infants that survive are often left with lifelong deficits in cognition, development, end organ function, behavioral milestones and/or other complications due to the intensity of treatment (Pui, NEJM 2003; Chow, J Pediatr 2007). The incidence rate of IL is increasing (Linabery, Cancer 2008) in the US, but cannot be attributed to chromosomal anomalies (Uckun, Blood 1998), environmental exposures (Ross, Epidemiol Rev 1994), or highly penetrant genetic polymorphisms alone. Clearly, a critical component of IL pathophysiology remains undiscovered. Rare variation has been implicated in a host of complex phenotypes and diseases, but the impact of rare germline variants on the etiology and outcome of IL has not been fully explored. The Rare Variant Hypothesis predicts that a population of affected individuals would harbor a diverse collection of functionally significant variants in genes involved in etiologically relevant pathways. Given this model, we hypothesize that the onset of IL requires heritable deleterious germline variants, which act alone or in combination with somatic mutations to induce leukemic transformation. Methods: To explore this possibility, we completed a pilot exome sequencing project on 25 pairs of germline DNA from mothers and their infants with MLL-negative IL collected from the Children's Oncology Group (COG) AE24 “Epidemiology of Infant Leukemia” study. Twelve infants had ALL, 13 had AML and none of the mothers had cancer. We asked if a) infants harbored rare or novel deleterious germline variants in known leukemia genes, b) these variants were inherited from mothers and c) the genes affected by these germline variants fell in common pathways or share common regulatory mechanisms. Results: We found an average of 16,056 variants per exome with an average of 3,082 (19.2%) being novel. Comparing these results to the COSMIC database (http://www.sanger.ac.uk/genetics/CGP/cosmic/), infants with AML had novel, non-synonymous, deleterious germline variants in 82 genes associated with hematologic malignancies, infants with ALL had similar variants in 64 genes, and 42 additional genes (40%) overlapped between ALL or AML. For infants with ALL, 45% of these variants were inherited from healthy mothers compared to only 23% in AML infants. Presumably, the remaining variants were inherited from fathers, but without paternal DNA, we cannot exclude de novo germline mutation, although such mutations are exceedingly rare and would only account for a few non-maternal variants. We used the g:Profiler (http://biit.cs.ut.ee/gprofiler/) algorithm to determine if any of these genes acted in common leukemia-related pathways or shared regulatory mechanisms. We found that many candidate genes were regulated by microRNAs (MIR) previously implicated in cancer, including MIR10a, MIR29c, MIR291b-3p, MIR369-5p, MIR469, MIR519a, MIR721. Five MIRs have been associated with leukemia, four with acute leukemia. Two MIRs, 291b-3p and 721, are also associated with embryonic stem cell cycle regulation and apoptosis, respectively. Ongoing work is focusing on additional exome sequencing, epidemiologic analysis and in vitro functional studies. Conclusion: It is clear that the incidence, clinical behavior and outcomes of IL cannot be explained fully through either environmental exposures or somatic mutations alone. We are leveraging the largest epidemiologic study of IL to date to explore the intersection of functional congenital genetic variation, clinical outcomes and maternal prenatal/pregnancy exposures to augment our understanding of IL. A better understanding of the natural history of IL will aid in future recommendations for pre- and post-natal genetic diagnostics, risk stratification of affected infants and ultimately therapeutic decisions. Disclosures: No relevant conflicts of interest to declare.
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Law, Matthew H., Lauren G. Aoude, David L. Duffy, Georgina V. Long, Peter A. Johansson, Antonia L. Pritchard, Kiarash Khosrotehrani, et al. "Multiplex melanoma families are enriched for polygenic risk." Human Molecular Genetics 29, no. 17 (July 27, 2020): 2976–85. http://dx.doi.org/10.1093/hmg/ddaa156.
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Abstract Cancers, including cutaneous melanoma, can cluster in families. In addition to environmental etiological factors such as ultraviolet radiation, cutaneous melanoma has a strong genetic component. Genetic risks for cutaneous melanoma range from rare, high-penetrance mutations to common, low-penetrance variants. Known high-penetrance mutations account for only about half of all densely affected cutaneous melanoma families, and the causes of familial clustering in the remainder are unknown. We hypothesize that some clustering is due to the cumulative effect of a large number of variants of individually small effect. Common, low-penetrance genetic risk variants can be combined into polygenic risk scores. We used a polygenic risk score for cutaneous melanoma to compare families without known high-penetrance mutations with unrelated melanoma cases and melanoma-free controls. Family members had significantly higher mean polygenic load for cutaneous melanoma than unrelated cases or melanoma-free healthy controls (Bonferroni-corrected t-test P = 1.5 × 10−5 and 6.3 × 10−45, respectively). Whole genome sequencing of germline DNA from 51 members of 21 families with low polygenic risk for melanoma identified a CDKN2A p.G101W mutation in a single family but no other candidate high-penetrance melanoma susceptibility genes. This work provides further evidence that melanoma, like many other common complex disorders, can arise from the joint action of multiple predisposing factors, including rare high-penetrance mutations, as well as via a combination of large numbers of alleles of small effect.
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Švajdler, Peter, Peter Vasovčák, Marián Švajdler, Monika Šedivcová, Veronika Urbán, Michal Michal, and Roman Mezencev. "CHEK2p.I157T Mutation Is Associated with Increased Risk of Adult-Type Ovarian Granulosa Cell Tumors." Cancers 14, no. 5 (February 25, 2022): 1208. http://dx.doi.org/10.3390/cancers14051208.
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Pathogenic germline mutations c.1100delC and p.I157T in the CHEK2 gene have been associated with increased risk of breast, colon, kidney, prostate, and thyroid cancers; however, no associations have yet been identified between these two most common European founder mutations of the CHEK2 gene and ovarian cancers of any type. Our review of 78 female heterozygous carriers of these mutations (age > 18 years) found strikingly higher proportion of adult-type granulosa cell tumors of the ovary (AGCTs) among ovarian cancers that developed in these women (~36%) compared to women from the general population (1.3%). Based on this finding, we performed a cross-sectional study that included 93 cases previously diagnosed with granulosa cell tumors, refined and validated their AGCT diagnosis through an IHC study, determined their status for the two CHEK2 mutations, and compared the prevalence of these mutations in the AGCT cases and reference populations. The prevalence ratios for the p.I157T mutation in the AGCT group relative to the global (PR = 26.52; CI95: 12.55–56.03) and European non-Finnish populations (PR = 24.55; CI95: 11.60–51.97) support an association between the CHEK2p.I157T mutation and AGCTs. These rare gynecologic tumors have not been previously associated with known risk factors and genetic predispositions. Furthermore, our results support the importance of the determination of the FOXL2p.C134W somatic mutation for accurate diagnosis of AGCTs and suggest a combination of IHC markers that can serve as a surrogate diagnostic marker to infer the mutational status of this FOXL2 allele.
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Campos, Fernando Augusto Batista, Etienne Rouleau, Giovana Tardin Torrezan, Dirce Maria Carraro, José Claudio Casali da Rocha, Higor Kassouf Mantovani, Leonardo Roberto da Silva, et al. "Genetic Landscape of Male Breast Cancer." Cancers 13, no. 14 (July 15, 2021): 3535. http://dx.doi.org/10.3390/cancers13143535.
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Male breast cancer (MBC) is now considered molecularly different from female breast cancer (FBC). Evidence from studies indicates that common genetic and epigenetic features of FBC are not shared with those diagnosed in men. Genetic predisposition is likely to play a significant role in the tumorigenesis of this rare disease. Inherited germline variants in BRCA1 and BRCA2 account for around 2% and 10% of MBC cases, respectively, and the lifetime risk of breast cancer for men harboring BRCA1 and BRCA2 mutations is 1.2% and 6.8%. As for FBC, pathogenic mutations in other breast cancer genes have also been recently associated with an increased risk of MBC, such as PALB2 and CHEK2 mutations. However, while multigene germline panels have been extensively performed for BC female patients, the rarity of MBC has resulted in limited data to allow the understanding of the magnitude of risk and the contribution of recently identified moderate penetrance genes of FBC for MBC predisposition. This review gathers available data about the germline genetic landscape of men affected by breast cancer, estimated risk associated with these genetic variants, and current guidelines for clinical management.
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Jackson, Aimee L., and Lawrence A. Loeb. "The Mutation Rate and Cancer." Genetics 148, no. 4 (April 1, 1998): 1483–90. http://dx.doi.org/10.1093/genetics/148.4.1483.
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Abstract The stability of the human genome requires that mutations in the germ line be exceptionally rare events. While most mutations are neutral or have deleterious effects, a limited number of mutations are required for adaptation to environmental changes. Drake has provided evidence that DNA-based microbes have evolved a mechanism to yield a common spontaneous mutation rate of ~0.003 mutations per genome per replication (Drake 1991). In contrast, mutation rates of RNA viruses are much larger (Holland et al. 1982) and can approach the maximum tolerable deleterious mutation rate of one per genome (Eigen and Schuster 1977; Eigen 1993). Drake calculates that lytic RNA viruses display spontaneous mutation rates of approximately one per genome while most have mutation rates that are approximately 0.1 per genome (Drake 1993). This constancy of germline mutation rates among microbial species need not necessarily mean constancy of the somatic mutation rates. Furthermore, there need not be a constant rate for somatic mutations during development. In this review, we consider mutations in cancer, a pathology in which there appears to be an increase in the rate of somatic mutations throughout the genome. Moreover, within the eukaryotic genome, as in microbes, there are “hot-spots” that exhibit unusually high mutation frequencies. It seems conceivable to us that many tumors contain thousands of changes in DNA sequence. The major question is: how do these mutations arise, and how many are rate-limiting for tumor progression?
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Wong, Richard, Shulei Sun, Huan-You Wang, Helen E. Broome, Sarah Murray, and John Thorson. "In Frame Calr Exon 9 Mutations: Often Ignored but Potentially Significant." Blood 132, Supplement 1 (November 29, 2018): 5480. http://dx.doi.org/10.1182/blood-2018-99-119897.
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Abstract Philadelphia chromosome negative myeloproliferative neoplasms (MPNs) are characterized by the overproduction of mature blood cells and variable bone marrow fibrosis. MPNs attributed to dysregulation of the Janus kinase 2 (JAK2) pathway include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Somatic mutations in JAK2, thrombopoietin receptor (MPL), and calreticulin (CALR) have been identified as driver mutations with direct or upstream upregulation of JAK2. CALR mutations are the most recently described, with the two most common mutations being a 52-base pair (bp) deletion (type 1) or 5 bp insertion (type2) in exon 9. Studies have shown a prognostic advantage to type1/type 1 like CALR driven MPNs over JAK2, MPL, and type2 CALR driven MPNs. Rarer CALR exon 9 mutations have also been identified in presumed MPN patients negative for JAK2 and MPL mutations. In these cases variable predicted changes to the CALR protein have resulted in speculative interpretations as to their relevance in the diagnosis of a suspected MPN. Here we report a patient with a longstanding history of myelofibrosis, thrombocytosis, and anemia, eventually determined to have an in-frame presumed germline (due to variant fraction and identification in the patient's child) CALR mutation downstream of a somatic type 1 CALR mutation. The overall compounded alterations generate a type 1 like mutation previously not described (to the best of our knowledge) in the literature. The patient is a 70-year old female noted to be persistently anemic all her life. While a bone marrow assessment was recommended early in life, the patient declined workup until a marrow biopsy was eventually performed at age 50. The biopsy reportedly showed mild marrow fibrosis and the patient was trailed on erythropoietin for her anemia with little benefit. At age 59 the patient was noted with thrombocytosis (478 X 109/L) and mild splenomegaly. Repeat marrow biopsy showed hypercellular marrow, marked fibrosis (WHO grade 3/3), and megakaryocyte clustering. JAK2 was noted to not be mutated. Over the next decade the patient developed symptomatic splenomegly and continued to be anemic with eventual intermittent transfusion requirement at age 65, pushing her risk to DIPPS-plus intermediate-2. During this period successive treatments included Revlimid, trial sonic hedgehog (shh) inhibitor, and JAK2 inhibitors with intervening multiyear long spans without treatment. Marrow fibrosis over this time was predominantly unchanged on the various therapies but symptomatic splenomegaly decreased on shh and JAK2 inhibitors. At present the patient requires intermittent transfusions and is on a JAK2 inhibitor. Recent NGS testing of marrow aspirate identified an in-frame presumed germline CALR mutation downstream of a compound somatic type 1 CALR mutation. A high molecular risk ASXL1 mutation was also identified. The in-frame CALR mutation results in a 9bp in frame deletion (c.1191_1199del, p.398_400delGluGluAsp), which has been reported at least 10 times in the literature. The various reports have one event mentioned as being presumably germline and non-pathogenic, while the other reports are equivocal to presumed pathogenic in light of negative JAK2 and MPL mutations in patients with clinical suspicion for a MPN. At our institution we have identified 4 instances of this 9bp deletion, 3 show allele fractions suggestive of being germline and 1 case with an allele fraction consistent with being a somatic mutation. In one germline case the patient also had a JAK2 V617F mutation and a diagnosis of a MPN. The other presumed germline case was found in an offspring of the patient described in this report and currently shows no signs of a MPN. The presumed somatic 9bp deletion was seen in patient with a hypocellular marrow myelodysplastic syndrome, found to also have a TET2 mutation and normal karyotype. While in-frame CALR exon 9 mutations are rare and predominantly considered germline non-pathogenic polymorphisms, there may be value in reporting such events in the context of patients with myeloid neoplasms as to not miss possible disease modifying mutations which may become apparent when aggregating multi-institution data sets. The patient highlighted in this report exhibits a strikingly long and relatively indolent disease course, notably despite an adverse prognostic risk category and high molecular risk mutation. Disclosures No relevant conflicts of interest to declare.
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Maung, Kyaw Ze Ya, Paul Leo, Anna L. Brown, Mahmoud A. Bassal, Debora A. Casolari, Adam Ewing, Emma Duncan, et al. "Rare Variants Affecting the Fanconi Anaemia DNA Repair Genes Associate with Increased Risk for AML." Blood 128, no. 22 (December 2, 2016): 41. http://dx.doi.org/10.1182/blood.v128.22.41.41.
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Abstract While there have been extensive studies to define the roles of recurrent somatic mutations in AML, the contribution of germline variants to AML initiation and progression is less well established. DNA repair disorders often predispose patients to developing myeloid malignancies. In particular, biallelic mutations affecting FANC genes cause the recessive heritable bone marrow failure syndrome Fanconi Anemia (FA), which is associated with >800-fold increased risk of progression to AML. A recent explosion of cancer predisposition studies has also revealed the importance of germlineFANC variants in elevated cancer risk (Cancer Treat Rev 2012; 38:89). To investigate the role of FANC gene variants in AML we have performed a case-control study, analyzing rare, deleterious somatic and germline variants for the 19 FANC genes in adult AML and healthy controls cohorts. Whole exome sequencing was performed on diagnosis samples from 131 adult Caucasian AML patients from two major Australian centers, and a cohort of 329 healthy females. We identified rare Tier 1 variants using a minor allele frequency (MAF) < 0.001, as reported in common dbSNP137, 1000 Genome and NHLBI-ESP project databases. Combined Annotation Dependent Depletion algorithm (CADD, Nat Genet 2014; 46: 310) >10 was used to filter for FANC gene variants with high probability of pathogenicity. Sanger sequencing of matched tumour/non-tumour DNA showed the large majority of variants tested to be germline (90%), consistent with previous studies reporting that somatic FANC genes variants are extremely rare in AML (< 1%). Overall, we identified 52 FANC gene variants in 44 cases with 34% of AML cases carrying one or more variant. For independent validation we determined the presence of somatic and germline FANC variants in the TCGA AML cohort using an identical pipeline and filtering analysis. In line with our results, we found that 36% of TCGA AML patients carry at least one germline FANC variant. We investigated known disease-causing (D-C) variants in these two AML cohorts using the FA (FAMutdb) and breast cancer (kConFab and BIC) mutation databases. We found 8 D-C FANC variants in the Australian AML cohort and 5 in the TCGA cohort, with 1 variant present in both cohorts. Moreover, the frequency of D-C variants in our cohort of females with AML (n=51) is 13.7%, while the frequency in the healthy female cohort is 4.5%, comparable to that reported in the ESP database for female European-Americans (2.1%, Hum Mol Genet 2014; 23: 6815). Accordingly, we determined that deleterious FANC germline variants confer a significant increased risk of AML (P=0.018, OR=3.3 for the Australian AML cohort). Finally, we performed mutational burden analysis to investigate enrichment of variants associated with particular FANC genes across the AML cohort. This revealed a significant enrichment of FANCL variants in AML vs healthy controls (P=0.008, Figure 1). FANCL is the enzymatic component of the FA core complex that monoubiquitinates the FANCD2/I heterodimer initiating DNA repair, and its down-regulation has been linked to AML (Oncogene 2016; doi:10.1038). Several FANCL variants, found in our AML cohort, affect the catalytic RING domain and are of particular interest. These include a D-C null variant present in 2 patients, a frame shift variant in 2 patients who presented with AML at a very early age (27 and 46 years old), and a variant affecting a critical conserved residue required for monoubiquitination of FANCD2/I. In conclusion, we show enrichment of rare potentially deleterious FANC gene mutations in AML, associated with a 3-fold increased risk of developing the disease. We hypothesise that, in hematopoietic stem/progenitor cells, these variants confer a subtle defect in interstrand cross-link repair leading to an increased accumulation of mutations and subsequent development of AML. Consistent with this there have been several reports of defective DNA damage repair and increased sensitivity to DNA damaging agents in cells from FANC carriers compared to normal controls (Nat Commun 2014; 5:5496; Mutagenesis 2009; 24:67). Importantly, it is possible to target defects in several DNA repair pathways, and our finding identifies a group of AML patients who may benefit from approaches that target defective FA and homologous recombination pathways. Figure 1. A significant increase mutational burden of FANCL was observed in our AML cohort (line represents P=0.05). Figure 1. A significant increase mutational burden of FANCL was observed in our AML cohort (line represents P=0.05). Disclosures Gill: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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Király, Péter Attila, Krisztián Kállay, Dóra Marosvári, Gábor Benyó, Anita Szőke, Judit Csomor, and Csaba Bödör. "Familiáris myelodysplasiás szindróma és akut myeloid leukaemia klinikai és genetikai háttere." Orvosi Hetilap 157, no. 8 (February 2016): 283–89. http://dx.doi.org/10.1556/650.2016.30375.
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Myelodysplastic syndrome and acute myeloid leukaemia are mainly sporadic diseases, however, rare familial cases exist. These disorders are considered rare, but are likely to be more common than currently appreciated, and are characterized by the autosomal dominant mutations of hematopoietic transcription factors. These syndromes have typical phenotypic features and are associated with an increased risk for developing overt malignancy. Currently, four recognized syndromes could be separated: familial acute myeloid leukemia with mutated CEBPA, familial myelodysplastic syndrome/acute myeloid leukemia with mutated GATA2, familial platelet disorder with propensity to myeloid malignancy with RUNX1 mutations, and telomere biology disorders due to mutations of TERC or TERT. Furthermore, there are new, emerging syndromes associated with germline mutations in novel genes including ANKRD26, ETV6, SRP72 or DDX41. This review will discuss the current understanding of the genetic basis and clinical presentation of familial leukemia and myelodysplasia. Orv. Hetil., 2016, 157(8), 283–289.
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Akhavanfard, Sara, Lamis Yehia, Roshan Padmanabhan, Todd Romigh, Ying Ni, and Charis Eng. "Germline EGFR mutation and cancer predisposition in adolescent and young adult (AYA) females with adrenocortical carcinoma." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e13014-e13014. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e13014.
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e13014 Background: Adrenocortical Carcinoma (ACC) is a rare endocrine tumor with poor overall prognosis and slight overrepresentation in females. In children, ACC is associated with inherited cancers, predominantly Li-Fraumeni syndrome, with 50-80% of childhood ACC harboring TP53 germline mutations. ACC in AYA are rarely due to germline TP53 mutations; IGF2, PRKAR1A and MEN1 are other less common germline mutated genes in this age group. Methods: We analyzed exome sequencing data from 21 children (C, < 15y), 32 AYA (15-39y), and 60 adult patients ( > 39y) with ACC, originating from the Cleveland Clinic, and TCGA and St. Jude’s datasets. We utilized the Integrative Variant Analysis platform to classify variants based on the American College of Medical Genetics guidelines. We retained all pathogenic, likely pathogenic, and highly-prioritized Variants of Uncertain Significance. Results: Pathway analysis on prioritized variants showed EGFR and p53 pathways as the two top pathways among our C-AYA patients. We found that 4.8% of children and 6.2% of AYA, all female patients, harbored a non-kinase-domain germline EGFR mutation, compared to only 1.7% of adult patients with ACC. As proof-of-principle functional validation, we engineered a lentiviral-mutant stable ACC-cell line, harboring an EGFR variant from a 21 y/o female with aggressive bilateral ACC (p.Asp1080Asn), without germline TP53 mutation. We showed that mutant cells grow slower, yet migrate faster and are characterized by a stem-like phenotype compared to wildtype cells. Osimertinib, among all tested EGFR inhibitors, resulted in the highest growth inhibition of mutant cells. While EGFR inhibitors had no effect on the stemness of mutant cells, Sunitinib, a multi-receptor tyrosine kinase inhibitor, significantly reduced the stem-like behavior. Conclusions: Our data suggest that EGFR is a novel underlying germline predisposition factor for ACC, especially in the female C-AYA population. Although our pre-clinical observations need to be further validated, identifying a targetable gene for ACC has the potential to improve precision oncology management of this disease, which is known to have limited therapeutic options.
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Myers, Kasiani C., Adam S. Nelson, Brian Sheehan, Maggie Malsch, Gwendolyn Towers, Audrey Anna Bolyard, Joan Moore, et al. "Germline and Somatic Genetic Characterization of Shwachman-Diamond Syndrome." Blood 128, no. 22 (December 2, 2016): 2681. http://dx.doi.org/10.1182/blood.v128.22.2681.2681.
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Abstract The North American Shwachman-Diamond Syndrome Registry (SDSR) opened in 2008 to improve our understanding of the natural history of Shwachman-Diamond Syndrome (SDS), improve medical outcomes, and facilitate research. The diagnosis of SDS was defined by either biallelic SBDS gene mutations or by the clinical combination of exocrine pancreatic dysfunction with bone marrow failure. Median age of study subjects is 11.2 years (range, 0.6-52.8). SBDS genetic reports were available for 168 subjects. Eighty-one had biallelic SBDS mutations, while 48 individuals lacked SBDS mutations. Ongoing characterization of SBDS mutation-negative individuals has identified subgroups of SDS individuals meeting clinical diagnostic criteria as outlined above, as well as a more heterogenous subgroup with features of SDS but in whom a clinical diagnosis could not be confirmed by classic diagnostic criteria. Amongst those with biallelic SBDS mutations, cytopenias were noted in all but 1 subject. Intermittent neutropenia was noted in 97% (n=70/72) and was the most frequent hematologic abnormality. Anemia was noted in 53% (n=39/73) and thrombocytopenia in 64% (n=48/75). Congenital anomalies were seen in 50% (n=39/78). The mutational spectrum of SBDS was explored. In 80 of 81 patients harboring biallelic SBDS mutations, the c.258+2 T>C intron 2 splice donor mutation was found in at least one of the two mutant SBDS alleles. In these cases, the mutation spectrum of the second mutant SBDS allele included missense mutations, splice site mutations, and truncating mutations. The one patient lacking the intron 2 splice donor mutation had a c.183_184delTAinsCT mutation together with a c.523 C>T mutation in SBDS confirmed to be in trans. This results in the combination of a truncating p.Lys62X mutation with a p.R175W missense mutation at a conserved residue predicted to be deleterious. This patient presented with neonatal severe aplastic anemia requiring platelet and red cell transfusions with neutrophil counts of 0-200 unresponsive to G-CSF. The marrow showed irregular islands of cartilage surrounded by osteoid consistent with a disorder of bone formation. A low level of SBDS protein is expressed by the c.258+2T>C variant, so the absence of this hypomorphic allele may have contributed to this exceptionally severe phenotype. Bone marrow reports were available for 67 subjects with biallelic SBDSmutations. Marrow hypocellularity was noted in 79% (n=49/62). Mild morphologic marrow dysplasia was observed in 58% (n=35/60). Clonal abnormalities developed in 36%. The most common clonal abnormality was del20q in 16% (n=10/64). Isochromosome 7 was noted in 2% (n=1/64). Three individuals developed AML at ages 19.5, 38, and 39 years. Eleven (14%) have undergone hematopoietic stem cell transplantation (HSCT), 10 for MDS or AML and 1 for severe aplastic anemia. Given the frequency of del20q clones in SDS, we studied clinical features of the 10 SDSR subjects with del20q clones. Median age of this group was 17 years (range, 10.8-29.3). Congenital anomalies were noted in 80% (n=8/10). Frequency of cytopenias was similar to that of non-del20q subjects, with neutropenia, anemia and thrombocytopenia seen in 90%, 50%, and 80% respectively. Bone marrow pathology reports were available for 9 subjects. All were noted to have hypocellular marrows as well as mild marrow dysplasia. In many patients, the clone was persistent or grew over time, with longest duration of 14.6 years. Progression to MDS was reported in 3 subjects who initially had an isolated del20q clone. Two developed an additional loss of chromosome 7. Progressive marrow dysplasia and falling blood counts were seen in two subjects. All three were treated with HSCT at 5.4, 5.7 and 7 years. Deletion of 20q in SDS has been hypothesized to result in a milder hematologic phenotype due to compensatory deletion of eIF6. eIF6 binds to the nascent 60S ribosomal subunit and sterically inhibits joining of the 60S to the 40S ribosomal subunits. SBDS functions to facilitate release of eIF6 thus promoting assembly of the mature 80S ribosome. These data from the SDSR suggest that SDS patients with del20q clones remain at risk for clonal evolution. Higher patient numbers are needed to quantitate risk of MDS in SDS patients with del20q. The SDSR continues to expand and mature as a resource for biological and clinical studies in this rare disorder advancing our understanding of marrow failure and clonal evolution. Disclosures Davies: Novartis: Honoraria. Dale:Amgen: Consultancy, Honoraria, Research Funding.
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Eldfors, Samuli, Mika Kontro, Kimmo Porkka, Olli Kallioniemi, and Caroline Heckman. "Landscape of Mutations in Relapsed Acute Myeloid Leukemia." Blood 124, no. 21 (December 6, 2014): 2367. http://dx.doi.org/10.1182/blood.v124.21.2367.2367.
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Abstract While the majority of acute myeloid leukemia (AML) patients respond to induction chemotherapy, disease recurrence and drug resistance is common. Recently, mutations underlying AML pathogenesis have been extensively characterized by sequencing large numbers of samples obtained at diagnosis. However, mutations driving disease progression and drug resistance in relapsed AML are not well characterized. In addition, understanding the clonal composition of relapsed AML is compounded by interference of donor cell variants present in those patients who have received an allogeneic hematopoietic stem cell transplant (alloHSCT). In this study we sought to identify mutations and copy number aberrations associated with development of drug resistant AML, and at the same time develop methods to identify and filter out donor variants. For the study we analyzed samples from patients who had relapsed after therapy (N=18) by exome sequencing. This included a set of patients where diagnosis and relapse samples were available (n=10), and one patient with diagnosis, remission and relapse samples. All patients had received prior chemotherapy and a subset had relapsed after receiving an allogeneic hematopoietic stem cell transplant (alloHSCT, n=6). Four patients had secondary AML that had developed after treatment for earlier hematologic malignancy. Tumor DNA was from bone marrow mononuclear cells and germline DNA from matched skin biopsies. Exome libraries were prepared then sequenced with the Illumina HiSeq instrument. Sequence data was processed and somatic variants identified as described previously (Koskela et al., NEJM, 2012). We identified relapse specific and relapse enriched somatic mutations by comparing mutation profiles of diagnosis and relapse samples. Donor derived germline variants in chimeric samples from patients relapsing after alloHSCT were identified with a bioinformatic methodology utilizing the dbSNP population variant database. Somatic mutations called from chimeric samples were filtered for common population variants present in the donor’s genome. Rare donor derived population variants that have not been previously described were identified as variants not present in the patient’s germline genome and which had similar tumor variant allele frequencies as the common donor derived variants. We estimated the level of chimerism based on the variant allele frequencies of all donor derived variants. In chimeric samples, the number of donor derived variants vastly exceeded the number of somatic mutations in AMLs (Fig 1). Donor cell content varied widely ranging from close to 100% in a post transplant remission sample to 10-40% in relapse samples. In post-transplant samples, we identified on average 6800 donor germline variants within the exome-capture regions, many of which occurred within cancer genes which could potentially be misinterpreted as driver mutations. Many recurrent driver mutations in cancer genes were identified in the relapse samples: FLT3 (n=6, 33%), DNMT3A (n=4, 22%), NPM1 (n=2, 11%), WT1 (n=2, 11%), TP53 (n=2, 11%), CBL (n=2, 11%), NRAS (n=1, 6%), KRAS (n=1, 6%), IDH1 (n=1, 6%), PHF6 (n=1, 6%) and PTPN11 (n=1, 6%). In several cases, we observed that relapse-specific driver mutations occurred in the same genes or pathways that already had initial mutations at diagnosis. For example, one patient’s AML had a FLT3-ITD at diagnosis; at relapse an activating mutation in CBL and a loss of function mutation in PTPN11 were acquired. Both CBL and PTPN11 act downstream of FLT3 (Fig 2). In two patients with a heterozygous WT1 mutation at diagnosis, we found additional WT1 mutations or deletion of the remaining wild type allele in the relapse sample, suggesting full loss of normal WT1 function contributes to disease progression. Our results suggest that AML progression and drug resistance may be caused by strengthening aberrant signaling through pathways already affected by a mutation present at diagnosis. Hence, the pattern of mutual exclusivity of mutations to genes affecting the same pathway, which has been observed in diagnostic samples, does not occur at relapse. On the contrary, in several cases the relapse specific mutations affected genes in pathways already affected at diagnosis. In addition, we show that donor derived germline variants can be identified and filtered from exome sequence data. Figure 1 Figure 1. Disclosures Porkka: BMS: Honoraria; BMS: Research Funding; Novartis: Honoraria; Novartis: Research Funding; Pfizer: Research Funding. Kallioniemi:Medisapiens: Consultancy, Membership on an entity's Board of Directors or advisory committees.
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Randall, Megan, Kelly Burgess, Lela Buckingham, and Lydia Usha. "Exceptional Response to Olaparib in a Patient With Recurrent Ovarian Cancer and an Entire BRCA1 Germline Gene Deletion." Journal of the National Comprehensive Cancer Network 18, no. 3 (March 2020): 223–28. http://dx.doi.org/10.6004/jnccn.2019.7378.
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PARP inhibitors are known to be effective in patients with ovarian cancer (OC) and germline mutations in BRCA1 and BRCA2 genes (BRCA mutations). Little is known, however, about any correlation between the deletion size and location of the BRCA mutation and the response to PARP inhibitors. Women with OC commonly undergo genetic testing because the presence of a germline BRCA mutation impacts therapeutic decisions and is important for cancer surveillance in patients and their family members. This report presents a case of a rare entire germline BRCA1 gene deletion and an exceptional response to a PARP inhibitor, olaparib, in a heavily pretreated patient with OC. Her disease course was also remarkable for complete responses to platinum-based chemotherapy and long chemotherapy-free intervals. Interestingly, the deletion of the entire BRCA1 gene was found after previously negative BRCA test results and is associated with a deletion of 6 adjacent genes without known clinical significance. She has remained progression-free and asymptomatic for >3 years on olaparib, with an overall survival of >12 years. We postulate that this unusually favorable response and prolonged overall survival is related to the cancer cells’ inability to reverse the entire gene deletion to wild-type (a common mechanism of resistance to PARP inhibition). This case shows the value of genetic testing for patients with OC and highlights the utility of additional testing with previously negative results and limited genetic testing. It also provides insight into a potential mechanism of an exceptional response to PARP inhibition.
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Ramamurthy, Chethan, Edward D. Esplin, Shan Yang, Michael Liss, Gail Elizabeth Tomlinson, and Guru Sonpavde. "Germline alterations in patients with testicular cancer." Journal of Clinical Oncology 38, no. 6_suppl (February 20, 2020): 397. http://dx.doi.org/10.1200/jco.2020.38.6_suppl.397.
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397 Background: There are limited data for the association of testis cancer (TC) with hereditary cancer genes. We report the prevalence of germline mutations among men with TC completing germline genetic testing through a large, commercial laboratory. Methods: We reviewed a de-identified dataset of men from across the USA with history of TC who underwent testing of 1 to 130 genes via massively parallel sequencing with customized capture bait-sets to analyze exonic regions, flanking intronic sequences, and copy number alterations. Pathogenic (P) and likely pathogenic (LP) were confirmed using orthogonal technology in accordance with Invitae standard operating practices. P/LP variants including single nucleotide variants/indels/copy number variants are reported. Fisher’s Exact test was used to analyze categorical variables. Results: The cohort of 250 men was 84% White/Caucasian. The median number of genes tested was 48. P/LP variants were found in 18% (n = 45) of subjects. P/LP variants occurred in several moderate to high penetrance genes, including CHEK2 (n = 10 [4.0%]), BRCA1/2 (n = 6 [2.4%]), ATM (n = 6 [2.4%]) and Lynch syndrome genes (n = 4 [1.6%]). Heterozygous MUTYH (n = 6) and NTHL1 (n = 1) mutations were also found. DNA damage repair (DDR) mutations were found in 14.8% (n = 37) of subjects. Of the 45 carriers, 18 (40%) had no other personal cancer history while 27 (60%) had an additional primary cancer, but there was no significant association between having another primary and risk of carrying a mutation (p = 0.253). CHEK2 was the single most frequently mutated gene, with 2 of the low penetrance I157T mutations identified, but 8 other higher penetrance variants, including 2 1100delC mutations. Conclusions: A high percentage of hereditary cancer gene mutations were found in testicular cancer patients, many which were not associated with a history of another malignancy. Several mutations were in high penetrance DDR genes such as BRCA1/2 and Lynch genes, which may also serve as actionable targets. CHEK2 mutations were common, supporting prior data suggesting an association with testicular cancer. Further multigene panel testing in unselected patients and the study of association with histologic subtype, race, stage and family history is warranted.
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Myllymaki, Mikko, Robert A. Redd, Corey S. Cutler, Wael Saber, Zhen-Huan Hu, Tao Wang, Stephen R. Spellman, et al. "Telomere Length and Telomerase Complex Mutations Predict Fatal Treatment Toxicity after Stem Cell Transplantation in Patients with Myelodysplastic Syndrome." Blood 132, Supplement 1 (November 29, 2018): 796. http://dx.doi.org/10.1182/blood-2018-99-117031.
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Abstract Introduction: Identifying patients at high risk of fatal treatment toxicity is a central challenge in hematopoietic stem cell transplantation (HSCT). Objective metrics that enable more accurate prediction of non-relapse mortality (NRM) could inform clinical decisions about timing and modality of HSCT. Short telomere length, mediated by inherited or acquired factors, impairs cellular response to genotoxic and replicative stress. We therefore evaluated the impact of recipient telomere length on clinical outcomes based on treatment intensity in patients with myelodysplastic syndrome (MDS) receiving HSCT. Methods: We used qPCR to measure relative telomere lengths in whole blood DNA samples from 1514 patients who received allogeneic HSCT for MDS and were enrolled in the Center for International Blood and Marrow Transplant Research Repository. Within the cohort, patients age 40 and older were grouped into those with short (<25th), intermediate (25-75th) or long (>75th percentile) telomeres. To evaluate germline determinants of telomere length, we sequenced 7 genes involved in telomere maintenance and mutated in dyskeratosis congenita: TERC, TERT, DKC1, TINF2, NHP2, WRAP53 and CTC1. Putative germline variants were classified as "rare" if the allele frequency was <0.001 in all Genome Aggregation Database (gnomAD) populations. Results: Among patients age 40 and older (n=1267), those with short (HR 1.52, 1.24-1.85, p<0.001) or intermediate (HR 1.35, 1.13-1.61, p<0.001) telomere length had poor overall survival compared with those having long telomeres (Fig 1A). In a competing risks regression model, the adverse effect of shorter telomeres was driven by a significantly higher risk of NRM among patients with short (HR 1.57, 1.20-2.06, p=0.001) and intermediate (HR 1.32, 1.03-1.69, p=0.03) telomere length. The association between telomere length and NRM was evident in patients receiving myeloablative (MAC, p=0.002) but not reduced-intensity conditioning (RIC, p=0.2) regimens (Fig 1B). We observed no association between telomere length and disease relapse in patients receiving MAC or RIC regimens. In a multivariable regression model, the prognostic significance of telomere length was independent of clinical and genetic factors, including age, Karnofsky performance status, hematologic parameters, IPSS-R risk category, donor mismatch, donor age, and TP53 mutation. We identified 40 patients (2.6% of the cohort) with rare germline TERT variants. Patients with rare TERT variants had significantly shorter telomeres than patients with common (p=0.001) or no (p<0.0001) TERT variants and were diagnosed with MDS at an earlier age than patients with common (52.2 vs. 58.4 years, p=0.01) or no (52.2 vs. 57.9 years, p=0.01) TERT variants. The domain distribution of rare TERT variants mirrored that of validated pathogenic germline TERT mutations, primarily affecting the reverse transcriptase and C-terminal extension domains. Rare variants in TERC (0.4%) and DKC1 (0.2%) were also associated with shorter telomeres (p=0.02 and p=0.04, respectively). In total, we identified germline telomerase complex mutations in 49 of 1514 MDS patients (3.2%), even though only 1 patient had a clinical diagnosis of dyskeratosis congenita. Together, patients with telomerase complex mutations had shorter overall survival than those without mutations (unadjusted p=0.008), attributable to a marked increase in the risk of early NRM among those receiving MAC (1 year cumulative incidence of NRM 48% vs. 26%, p=0.03). The impact of shorter telomeres on NRM was similar in patients with and without identified core telomerase complex mutations, suggesting that additional mechanisms of impaired telomere length maintenance may contribute to MDS pathogenesis and outcome. Conclusion: Recipient telomere length is independently associated with overall survival after allogeneic HSCT for MDS. Patients age 40 or older with shorter blood cell telomere length have a significantly elevated risk of early NRM with myeloablative conditioning regimens. Clinically unrecognized germline mutations in the telomerase genes TERT, TERC, and DKC1 define a distinct subset of adult patients with sporadic MDS and short telomeres who have poor transplant outcomes. Together, these results indicate that short telomere length in MDS patients mediates fatal treatment toxicity that may be attenuated by lower intensity conditioning approaches. Disclosures Antin: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.
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Robinson, Giles W., Sebastian M. Waszak, Brian L. Gudenas, Kyle S. Smith, Antoine Forget, Marija Kojic, Garcia-Lopez Jesus, et al. "MBCL-21. GERMLINE ELONGATOR MUTATIONS IN SONIC HEDGEHOG MEDULLOBLASTOMA." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii392—iii393. http://dx.doi.org/10.1093/neuonc/noaa222.497.
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Abstract BACKGROUND Our previous analysis of established cancer predisposition genes in medulloblastoma (MB) identified pathogenic germline variants in ~5% of all patients. Here, we extended our analysis to include all protein-coding genes. METHODS Case-control analysis performed on 795 MB patients against >118,000 cancer-free children and adults was performed to identify an association between rare germline variants and MB. RESULTS Germline loss-of-function variants of Elongator Complex Protein 1 (ELP1; 9q31.3) were strongly associated with SHH subgroup (MBSHH). ELP1-associated-MBs accounted for ~15% (29/202) of pediatric MBSHH cases and were restricted to the SHHα subtype. ELP1-associated-MBs demonstrated biallelic inactivation of ELP1 due to somatic chromosome 9q loss and most tumors exhibited co-occurring somatic PTCH1 (9q22.32) alterations. Inheritance was verified by parent-offspring sequencing (n=3) and pedigree analysis identified two families with a history of pediatric MB. ELP1-associated-MBSHH were characterized by desmoplastic/nodular histology (76%; 13/17) and demonstrated a favorable clinical outcome when compared to TP53-associated-MBSHH (5-yr OS 92% vs 20%; p-value=1.3e-6) despite both belonging to the SHHα subtype. ELP1 is a subunit of the Elongator complex, that promotes efficient translational elongation through tRNA modifications at the wobble (U34) position. Biochemical, transcriptional, and proteomic analyses revealed ELP1-associated-MBs exhibit destabilization of the core Elongator complex, loss of tRNA wobble modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response. CONCLUSIONS We identified ELP1 as the most common MB predisposition gene, increasing the total genetic predisposition for pediatric MBSHH to 40%. These results mark MBSHH as an overwhelmingly genetically-predisposed disease and implicate disruption of protein homeostasis in MBSHH development.
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Doros, Leslie Ann, Jiandong Yang, Amanda Field, Christopher Rossi, Gretchen M. Williams, Kris Ann Pinekenstein Schultz, Louis P. Dehner, Yoav H. Messinger, and D. Ashley Hill. "Pleuropulmonary blastoma: The causative role of germ-line DICER1 mutations." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 10024. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.10024.
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10024 Background: Pleuropulmonary blastoma (PPB) is a rare, aggressive childhood lung cancer that is often the first manifestation of the PPB-DICER1 familial tumor predisposition which includes other benign and malignant conditions. The initial genetic mutation is inherited by a germ-line loss of function of DICER1 gene which was discovered by Hill et al. It is proposed that loss of DICER1 expression alters miRNA regulation of key regulatory cellular mechanisms which promote tumor growth. PPB can progress from the purely cystic, curable Type I to a high-grade Type III having a dismal prognosis. We sought to determine the frequency of DICER1mutation in the largest cohort of PPB patients to date. Methods: We obtained germ-line DNA from saliva or blood samples from 113 PPB patients collected from 2005-2012. DNA was extracted using the Maxwell 16 Research System (Promega Corporation, Madison WI). Sample quality and quantity was checked using the Nanodrop 2000 (Thermo Scientific, Wilmington, DE). Sequencing was performed using the Sanger sequencer. For a subset of cases we used targeted sequencing services or full gene sequence analysis (Ambry Genetics, Aliso Viejo, CA). Results: Seventy-four (65.5%) PPB patients were found to have deleterious DICER1germ-line mutations. The most common mutation type found was small insertion/deletions. These 74 samples were composed of 7 (9.5%)Type Ir PPBs, 22 (29.7%)Type I PPBs, 24 (32.4%) Type II PPBs, and 21 (28.4%)Type III PPBs. The following Table shows a summary of mutation types identified. Conclusions: Our results confirm that DICER1 germline mutations are the most common genetic alterations in PPB making it critical for genetic testing to be performed at diagnosis. Additionally, this underscores the need for important correlative studies to describe the genotype-phenotype relationship in order for appropriate screening guidelines to be developed and implemented to allow for early detection. While a majority of cases are explained by germline DICER1 mutations using current sequencing methods, further investigation is warranted to elucidate other possible mechanisms in the development of PPB. [Table: see text]
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Yu, Kai, Matthew Merguerian, Natalie Deuitch, Erica Bresciani, Joie Davis, Kathleen Craft, Lea C. Cunningham, and Paul P. Liu. "Genomic Landscape of RUNX1-Familial Platelet Disorder with Myeloid Malignancies Reveals Rising Clonal Hematopoiesis." Blood 138, Supplement 1 (November 5, 2021): 1090. http://dx.doi.org/10.1182/blood-2021-151781.
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Abstract Familial platelet disorder with associated myeloid malignancies (FPDMM) is a rare autosomal dominant disease caused by germline RUNX1 mutations. FPDMM patients have defective megakaryocytic development, low platelet counts, prolonged bleeding times, and a life-long risk (20-50%) of developing hematological malignancies. FPDMM is a rare genetic disease in need of comprehensive clinical and genomic studies. In early 2019 we launched a longitudinal natural history study of patients with FPDMM at the NIH Clinical Center and by May 2021 we have enrolled 98 patients and 100 family controls from 55 unrelated families. Genomic data have been generated from 56 patients in 24 families, including whole exome sequencing (WES), RNA-seq, and single-nucleotide polymorphism (SNP) array. We have identified 21 different germline RUNX1 variants among these 24 families, which include lost-of-function mutations throughout the RUNX1 gene, but pathogenic/likely pathogenic missense mutations are mostly clustered in the runt-homology domain (RHD). As an important form of RUNX1 germline mutations, five splice site variants located between exon 4-5 and exon 5-6 were identified in 6 families, which led to the productions of novel transcript forms that are predicted to generate truncated RUNX1 proteins. Large deletions affecting the RUNX1 gene are also common, ranging from 50 Kb to 1.5Mb, which were detected in 8 of the 55 enrolled families. Besides RUNX1, copy number variation (CNV) analysis from both SNP array and WES showed limited CNV events in non-malignant FPDMM patients. In addition, fusion gene analysis did not detect any in-frame fusion gene in these patients, indicating a relatively stable chromosome status in FPDMM patients. Somatic mutation landscape shows that the overall mutation burden in non-malignant FPDMM patients is lower than AML or other cancer types. However, in 13 of the 44 non-malignant patients (30%), somatic mutations were detected in at least one of the reported clonal hematopoiesis of indeterminate potential (CHIP) genes, significantly higher than the general population (4.3%). Moreover, 85% of our patients who carried CHIP mutations are under 65 years of age; in the general population, only 10% of people above 65 years of age and 1% of people under 50 were reported to carry CHIP mutations. Among mutated genes related to clonal hematopoiesis, BCOR is the most frequently mutated gene (5/44) in our FPDMM cohort, which is not a common CHIP gene among the general population. Mutations in known CHIP genes including SF3B1, TET2, and DNMT3A were also found in more than one patient. In addition, sequencing of 5 patients who already developed myeloid malignancies detected somatic mutations in BCOR, TET2, NRAS, KRAS, CTCF, KMT2D, PHF6, and SUZ12. Besides reported CHIP genes or leukemia driver genes, 3 unrelated patients carried somatic mutations in the NFE2 gene, which is essential for regulating erythroid and megakaryocytic maturation and differentiation. Two of the NFE2 mutations are nonsense mutations, and the other is a missense mutation in the important functional domain. NFE2 somatic mutations may play important roles in developing malignancy because 2 of the 3 patients already developed myeloid malignancies. For multiple patients in our cohort, we have sequenced their DNA on multiple timepoints. We have observed patients with expanding clones carrying FKBP8, BCOR or FOXP1 mutations. We have also observed a patient with relatively stable clone(s) with somatic BCOR, DNMT3A, and RUNX1T1, who have been sampled over more than four years. We will follow these somatic mutations through sequencing longitudinally and correlate the findings with clinical observations to see if the dynamic changes of CHIP clones harboring the mutations give rise to MDS or leukemia. In summary, the genomic analysis of our new natural history study demonstrated diverse types of germline RUNX1 mutations and high frequency of somatic mutations related to clonal hematopoiesis in FPDMM patients. These findings indicate that monitoring the dynamic changes of these CHIP mutations prospectively will benefit patients' clinical management and help us understand possible mechanisms for the progression from FPDMM to myeloid malignancies. Disclosures No relevant conflicts of interest to declare.
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Meerschaut, Ilse, Wouter Steyaert, Thierry Bové, Katrien François, Thomas Martens, Katya De Groote, Hans De Wilde, et al. "Exploring the Mutational Landscape of Isolated Congenital Heart Defects: An Exome Sequencing Study Using Cardiac DNA." Genes 13, no. 7 (July 7, 2022): 1214. http://dx.doi.org/10.3390/genes13071214.
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Congenital heart defects (CHD) are the most common congenital anomalies in liveborn children. In contrast to syndromic CHD (SCHD), the genetic basis of isolated CHD (ICHD) is complex, and the underlying pathogenic mechanisms appear intricate and are incompletely understood. Next to rare Mendelian conditions, somatic mosaicism or a complex multifactorial genetic architecture are assumed for most ICHD. We performed exome sequencing (ES) in 73 parent–offspring ICHD trios using proband DNA extracted from cardiac tissue. We identified six germline de novo variants and 625 germline rare inherited variants with ‘damaging’ in silico predictions in cardiac-relevant genes expressed in the developing human heart. There were no CHD-relevant somatic variants. Transmission disequilibrium testing (TDT) and association testing (AT) yielded no statistically significant results, except for the AT of missense variants in cilia genes. Somatic mutations are not a common cause of ICHD. Rare de novo and inherited protein-damaging variants may contribute to ICHD, possibly as part of an oligogenic or polygenic disease model. TDT and AT failed to provide informative results, likely due to the lack of power, but provided a framework for future studies in larger cohorts. Overall, the diagnostic value of ES on cardiac tissue is limited in individual ICHD cases.
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Banne, Ehud, Baraa Abudiab, Sara Abu-Swai, Srinivasa Rao Repudi, Daniel J. Steinberg, Diala Shatleh, Sarah Alshammery, et al. "Neurological Disorders Associated with WWOX Germline Mutations—A Comprehensive Overview." Cells 10, no. 4 (April 7, 2021): 824. http://dx.doi.org/10.3390/cells10040824.
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The transcriptional regulator WW domain-containing oxidoreductase (WWOX) is a key player in a number of cellular and biological processes including tumor suppression. Recent evidence has emerged associating WWOX with non-cancer disorders. Patients harboring pathogenic germline bi-allelic WWOX variants have been described with the rare devastating neurological syndromes autosomal recessive spinocerebellar ataxia 12 (SCAR12) (6 patients) and WWOX-related epileptic encephalopathy (DEE28 or WOREE syndrome) (56 patients). Individuals with these syndromes present with a highly heterogenous clinical spectrum, the most common clinical symptoms being severe epileptic encephalopathy and profound global developmental delay. Knowledge of the underlying pathophysiology of these syndromes, the range of variants of the WWOX gene and its genotype-phenotype correlations is limited, hampering therapeutic efforts. Therefore, there is a critical need to identify and consolidate all the reported variants in WWOX to distinguish between disease-causing alleles and their associated severity, and benign variants, with the aim of improving diagnosis and increasing therapeutic efforts. Here, we provide a comprehensive review of the literature on WWOX, and analyze the pathogenic variants from published and unpublished reports by collecting entries from the ClinVar, DECIPHER, VarSome, and PubMed databases to generate the largest dataset of WWOX pathogenic variants. We estimate the correlation between variant type and patient phenotype, and delineate the impact of each variant, and used GnomAD to cross reference these variants found in the general population. From these searches, we generated the largest published cohort of WWOX individuals. We conclude with a discussion on potential personalized medicine approaches to tackle the devastating disorders associated with WWOX mutations.
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Yeap, Isobel, Therese Becker, Farhad Azimi, and Michael Kernohan. "The management of hereditary melanoma, FAMMM syndrome and germline CDKN2A mutations: a narrative review." Australasian Journal of Plastic Surgery 5, no. 2 (September 30, 2022): 12–22. http://dx.doi.org/10.34239/ajops.v5n2.324.
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Familial atypical multiple mole melanoma (FAMMM) syndrome is a rare autosomal dominant disorder, in which patients present with a large number of melanocytic naevi and a strong history of malignant melanoma, usually at a young age. The most common genetic alteration, implicated in 40 per cent of FAMMM syndrome families, is a mutation of cyclin-dependent kinase inhibitor 2A (CDKN2A).1 CDKN2A encodes the tumour suppressor gene p16INK4a, a critical cell cycle inhibitor.2 The diagnosis and management of patients with FAMMM syndrome is relevant to the plastic surgeon who manages melanoma. However, clear guidelines on its diagnostic criteria and its relationship to associated but distinct syndromes, such as hereditary melanoma and B-K mole syndrome, are lacking in the extant literature. The aim of this review is to clarify the diagnostic criteria and management principles for FAMMM syndrome. We propose a new system of classifying FAMMM syndrome patients as a subset of all patients with hereditary melanoma. We also present a management algorithm for these distinct patient groups (FAMMM syndrome, hereditary melanoma and germline CDKN2A mutations).
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Baughn, Linda B., Scott Gilles, Elizabeth L. Courville, Andrew C. Nelson, and Zohar Sachs. "Germline Calr Mutation and Thrombocytosis Presenting with Concomitant BCR-ABL1+ CML." Blood 128, no. 22 (December 2, 2016): 5494. http://dx.doi.org/10.1182/blood.v128.22.5494.5494.
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Abstract CALR mutations are present in 70-84% of JAK2 wild-type myeloproliferative neoplasms (MPN) and 67% and 88% of essential thrombocytopenia (ET) and primary myelofibrosis (PMF) respectively. Most cases of MPN are apparently sporadic, but 7-11% have evidence of familial predisposition. While germline mutations in ET-associated genes, MPL and JAK2, have been described in hereditary thrombocytosis, germline mutations in CALR have not been described in any setting. Two types of CALR mutations are common in MPN: a 52-base pair deletion (bp) and a 5 bp insertion, both in exon 9. With rare exceptions, CALR mutations are generally mutually exclusive with JAK2 or MPL mutations and have very rarely been reported in conjunction with the BCR-ABL1translocation. Here, we report a patient with a germline CALR mutation, thrombocytosis, and subsequent development of BCR-ABL+ CML. A 67-year-old female with no significant medical history presented with severe abdominal pain and nausea. Peripheral blood analysis revealed a marked leukocytosis composed of 66% neutrophils, 16% myelocytes, 6.5% monocytes, 3.5% basophils, 2.5% promyelocytes, 2.5% metamyelocytes, 1.5% lymphocytes, 1.5% blasts, and no eosinophils. The patient was non-anemic and had a normal platelet count (340,000/mm3). Bone marrow biopsy revealed a hypercellular marrow with myeloid predominant trilineage hematopoiesis and 1-2% blasts with morphology consistent with chronic myelogenous leukemia (CML). Fluorescence in-situ hybridization analysis of peripheral blood identified a BCR-ABL1fusion in 98.5% of interphase cells. After 3 months of standard imatinib therapy, quantitative RT-PCR showed a reduction of BCR-ABL1/ABL1 in the peripheral blood, however platelet count was elevated at 539,000/mm3. Thrombocytosis persisted over 2 years with a maximal platelet count of 584,000/mm3. Given the patient's thrombocytosis, her peripheral blood was subjected to a next generation sequencing of JAK2, MPL, and CALR genes. A 52-bp out-of-frame deletion in exon 9 of the CALR gene was detected (52% allele frequency) in peripheral blood. In addition, the same 52-bp CALR deletion (63% allele frequency) was present at the time of diagnosis and within a buccal specimen (47% allele frequency) when the BCR-ABL1 transcript was 1% in the peripheral blood. Immunostain of the buccal sample was strongly positive for cytokeratin (CK) AE1/AE3 but CD45 was not detected indicating no leukocyte contamination. This case reports the first instance of a germline CALR mutation associated with thrombocytosis and is the fourth report of the co-occurrence of BCR-ABL1 and CALR mutation in a single patient. Evolution to BCR-ABL1+ CML suppressed the CALR-mutant thrombocytosis phenotype, emphasizing the effect of these genes on lineage determination in abnormal myeloid proliferation. Disclosures No relevant conflicts of interest to declare.
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Apostolou, Paraskevi, and Florentia Fostira. "Hereditary Breast Cancer: The Era of New Susceptibility Genes." BioMed Research International 2013 (2013): 1–11. http://dx.doi.org/10.1155/2013/747318.
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Breast cancer is the most common malignancy among females. 5%–10% of breast cancer cases are hereditary and are caused by pathogenic mutations in the considered referenceBRCA1andBRCA2genes. As sequencing technologies evolve, more susceptible genes have been discovered andBRCA1andBRCA2predisposition seems to be only a part of the story. These new findings include rare germline mutations in other high penetrant genes, the most important of which includeTP53mutations in Li-Fraumeni syndrome,STK11mutations in Peutz-Jeghers syndrome, andPTENmutations in Cowden syndrome. Furthermore, more frequent, but less penetrant, mutations have been identified in families with breast cancer clustering, in moderate or low penetrant genes, such asCHEK2,ATM,PALB2,andBRIP1. This paper will summarize all current data on new findings in breast cancer susceptibility genes.
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Brown, Jennifer R., Michael S. Lawrence, Megan Hanna, Bethany Tesar, Petar Stojanov, Alexander R. Vartanov, Stacey M. Fernandes, et al. "Novel Germline Genetic Variants Associated with Familial Chronic Lymphocytic Leukemia (CLL)." Blood 118, no. 21 (November 18, 2011): 465. http://dx.doi.org/10.1182/blood.v118.21.465.465.
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Abstract Abstract 465 CLL is among the most heritable of all cancers. To understand the genetic basis of this heritability, we have undertaken a comprehensive genomic analysis of familial CLLs including copy number analysis, gene expression profiling (GEP) and whole exome sequencing (WES). First, we examined whether familial and sporadic cases differ in the spectrum of acquired somatic mutations by WES of tumor and germline DNA of 36 familial CLLs (from 31 affected families). Compared to 55 sporadic CLLs, we observed that the somatic mutation rate in the familial CLLs was similar (mean 0.89 mutations/Mb (range 0.29–3.06) for the sporadics vs mean 0.97/Mb (range 0.11–3.78) for the familials, p=0.40). We also examined the spectrum of somatic mutations by testing for enrichment of 9 recently identified putative tumor drivers in our large CLL sequencing study (reported elsewhere in this meeting). We observed a similar distribution of these recurrent CLL mutations among the 36 familial CLLs as the 55 sporadic CLLs. These results were further confirmed by genotyping of the CLL driver mutations in an additional 32 familial and 67 sporadic CLLs. Collectively, these studies suggest that while the predisposing germline events may differ between familial and sporadic CLL, the spectrum of mutations and pattern of mutagenesis appear similar in the established CLL tumors. We therefore proceeded to examine the genetic characterization of germline DNA to identify predisposing loci, which we hypothesized might be enriched in a familial disease context. We first examined germline copy number variations (CNVs), which have not been previously characterized in this disease. We used high resolution Affymetrix 6.0 SNP arrays to study both tumor and germline DNA of 58 individuals representing 44 different families with CLL and lymphoproliferative disorders (LPDs). We identified two families (A and B) with autosomal dominant inheritance of CLL who carried distinct germline CNVs that affect genes previously implicated in CLL. Members of Family A carried a 525 kb germline deletion targeting DLEU7 at 13q14, but not affecting DLEU2, miR-15a, or miR-16–1. Importantly, by examining the tumor genome from these family members, we observed a uniform loss of the second allele of DLEU7 in 2/2 available CLLs from this family, suggesting an acquired “second hit” of a tumor suppressor gene. These findings underline the complexity of the most common somatically acquired copy number aberration (CNA) in CLL, 13q14 deletion, by demonstrating the role of additional regions other than the heavily investigated miRNA cluster. Members of Family B carried a 720 kb germline gain of 6p25 affecting the IRF4 gene, previously implicated in CLL through the identification of a GWAS risk allele located in the 3' UTR of IRF4, as well as the recent description of a recurrent somatic mutation affecting 1.5% of CLL cases. In Family B, the coding regions of the four genes located in this 6p gain, namely IRF4, DUSP22, EXOC2 and HUS1B, were sequenced, and no somatic mutations or novel SNPs were identified. However, the 6p gain in Family B represents an allele-specific enrichment of the haplotype carrying the GWAS risk SNP and, as previously described for that allele, results in lower expression of IRF4 in the two CLLs tested in this family. GEP further identified a signature associated with 6p gain that preserved low expression of IRF4 and showed high expression of KLF6. These results demonstrate that germline CNVs may facilitate the “path to cancer” by providing either an allelic deletion of a tumor suppressor or an amplification of a risk allele. As most familial CLL cases have not been accounted for by known SNPs or germline CNVs, we have initiated an in depth analysis of the WES germline results from familial cases compared to both sporadic CLL patients and normal individuals. Candidate variants have been filtered to exclude all SNPs described in the 1000 Genomes project and to focus on highly conserved sites. Thus far we have found that rare germline variants in patients with familial CLL contain a rich source of loci with relevance to B cell biology. Studies in progress are focused on further analysis of informative families and functional analyses of candidate variants. These comprehensive genomic analyses are expected to identify multiple cooperating genetic mechanisms that contribute to CLL pathogenesis, including CNVs and somatic and germline mutations. Disclosures: No relevant conflicts of interest to declare.
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Raitila, A., M. Georgitsi, A. Karhu, K. Tuppurainen, M. J. Mäkinen, K. Birkenkamp-Demtröder, K. Salmenkivi, et al. "No evidence of somatic aryl hydrocarbon receptor interacting protein mutations in sporadic endocrine neoplasia." Endocrine-Related Cancer 14, no. 3 (September 2007): 901–6. http://dx.doi.org/10.1677/erc-07-0025.
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Germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene were recently observed in patients with pituitary adenoma predisposition (PAP). Though AIP mutation-positive individuals with prolactin-, mixed growth hormone/prolactin-, and ACTH-producing pituitary adenomas as well as non-secreting pituitary adenomas have been reported, most mutation-positive patients have had growth hormone-producing adenomas diagnosed at relatively young age. Pituitary adenomas are also component tumors of some familial endocrine neoplasia syndromes such as multiple endocrine neoplasia type 1 (MEN1) and Carney complex (CNC). Genes underlying MEN1 and CNC are rarely mutated in sporadic pituitary adenomas, but more often in other lesions contributing to these two syndromes. Thus far, the occurrence of somatic AIP mutations has not been studied in endocrine tumors other than pituitary adenomas. Here, we have analyzed 32 pituitary adenomas and 79 other tumors of the endocrine system for somatic AIP mutations by direct sequencing. No somatic mutations were identified. However, two out of nine patients with prolactin-producing adenoma were shown to harbor a Finnish founder mutation (Q14X) with a complete loss of the wild-type allele in the tumors. These results are in agreement with previous studies in that prolactin-producing adenomas are component tumors in PAP. The data also support the previous finding that somatic AIP mutations are not common in pituitary adenomas and suggest that such mutations are rare in other endocrine tumors as well.
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Tang, Tin-Yun, Duncan Stearns, Alexander Miron, and Anna Mitchell. "Pathogenic TP53 variant allele frequency across different somatic tissues in two patients with mosaic Li-Fraumeni." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 10582. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.10582.
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10582 Background: The integration of germline genetic testing, frequently from blood, into routine oncological care has increased the frequency at which pathogenic TP53 mutations are found in a variant allele frequency (VAF) range suggestive of either mosaic Li-Fraumeni Syndrome or clonal hematopoiesis of indeterminate potential (CHIP). Mosaic LFS is a rare and poorly described phenomenon wherein a pathogenic TP53 mutation is dispersed in low levels through multiple somatic tissues after stochastically developing during early embryogenesis. In comparison, CHIP is restricted to the bone marrow niche. Germline mosaicism in Li-Fraumeni Syndrome (LFS) is inferred when genomic DNA from a second source recapitulates the exact same TP53 mutation. Given the challenges with sample acquisition, mosaicism has not been previously described in depth in the medical literature. Methods: Two pediatric patients with LFS-associated cancers (glioblastoma, osteosarcoma & ALL respectively) underwent clinical genetics evaluation and were found to have pathogenic TP53 mutations. Initial genetic testing was performed in a CLIA/CAP environment through a send out test or internally. A broad array of somatic tissues was collected at autopsy with subsequent DNA isolation and amplicon sequencing in triplicate to determine the mean VAF of the pathogenic TP53 allele. Results: For both patients, the initial germline test suggesting mosaic LFS had a VAF between 20-30%. Confirmatory intent fibroblast culture in Patient 1 was reported as negative by an external clinical lab and Patient 2’s VAF was much lower. The VAFs for the rest of the somatic tissues as well as in their corresponding cancers are reported below (Table) as means and standard error of the triplicate. Despite the negative fibroblast culture, Patient 1 did demonstrate mutant TP53 in other tissues, confirming mosaicism. Conclusions: The proportion of pathogenic alleles is highly heterogeneous amongst different somatic tissues in mosaic LFS patients. Although CHIP exclusion through germline testing of cultured skin fibroblasts is common, our patients’ skin samples were amongst the tissues with the lowest VAFs. Mosaicism should be highly suspected when tumor sequencing demonstrates an identical mutation to the putative germline mosaic one even with equivocal fibroblast culture results. [Table: see text]
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Zeichner, Simon B., Naveen Raj, Mike Cusnir, Michael Francavilla, and Alicia Hirzel. "A De Novo Germline APC Mutation (3927del5) in a Patient with Familial Adenomatous Polyposis: Case Report and Literature Review." Clinical Medicine Insights: Oncology 6 (January 2012): CMO.S10178. http://dx.doi.org/10.4137/cmo.s10178.
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Introduction Characterized by the development of hundreds to thousands of colonic adenomas, classic familial adenomatous polyposis (FAP) is one of the most common hereditary syndromes associated with an increased risk of colorectal cancer. Several studies have attempted to correlate specific APC mutations with clinical phenotype. 6 However, there is considerable variability in the expression of specific phenotypes within families and among individuals with identical mutations. 7 Case Presentation A 30 year-old Hispanic female presented to the emergency department with a 2-week history of persistent, worsening, left lower quadrant abdominal pain. She had no family history of malignancy. Sigmoidoscopy revealed innumerable polyps in the rectum and sigmoid colon and a large mass in the sigmoid colon. Biopsy of the mass revealed a moderately differentiated adenocarcinoma invading the subserosa. Endoscopy revealed innumerable polyps. Genetic testing of the patient via southern blot revealed a germline APC mutation 3927del5, resulting in a premature truncation of the APC protein at amino acid position 1312. Conclusion Genetic information has only recently started being incorporated into clinical care. More research and randomized clinical trials need to be conducted to definitively characterize random mutations. Once these mutations are further understood, FAP patients may be able to be risk stratified and this may ultimately improve the screening, diagnosis, and treatment of this rare condition.
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Strauss, K., S. Smith, and A. Grover. "ARMC5-associated Bilateral Macronodular Adrenocortical Hyperplasia: A Novel Germline Variant Associated with Concomitant Papillary Thyroid Carcinoma and Meningioma." American Journal of Clinical Pathology 156, Supplement_1 (October 1, 2021): S54—S55. http://dx.doi.org/10.1093/ajcp/aqab191.111.
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Abstract Introduction/Objective Germline mutations in the tumor suppressor gene Armadillo-containing repeat protein 5 gene (ARMC5) have been very recently recognized as a cause for a familial form of bilateral macronodular adrenocortical hyperplasia (BMAH), itself a rare cause of Cushing syndrome. In patients with ARMC5 mutations, scattered case reports have also shown an association with meningiomas and cancers of the pancreas, breast, colon, and thyroid. Methods/Case Report We present the case of BMAH, arising in a 61-year-old female with a history of metastatic papillary thyroid carcinoma and meningioma. The patient presented with bilateral but asymmetric adrenal enlargement (right greater than left) and Cushing syndrome. Given history of thyroid cancer and meningioma, genetics referral was ordered. Counseling revealed a pedigree without a strongly evident familial pattern of hereditary endocrine neoplasia characteristic of any of the more common inherited dispositions to endocrine neoplasia. Additionally, a targeted capture-based NGS germline genetic sequencing study for variants in 12 genes associated with associated with hereditary thyroid cancer was performed and negative. However, based on recent scholarship regarding ARMC5, follow-up germline NGS and Sanger sequencing studies encompassing the entire coding sequences of ARMC5 were ordered. These identified a germline, heterozygous, novel (not in ClinVar) but likely pathogenic variant in (c.802C>T, p.Arg268*), providing a likely explanation for the patient’s BMAH. In attempt to control the patient’s Cushing symptoms, right-sided adrenalectomy was performed, revealing a 220g adrenal gland with marked multinodular hyperplasia with solid, nested, and tubular architecture. Results (if a Case Study enter NA) NA Conclusion While case reports exist describing an association between other ARMC5 mutations and BMAH with concomitant meningiomas and/or malignancies, greater study is needed in order to better characterize the phenotypic spectrum of this disease. Our experience with this case not only reports a novel, apparently pathogenic mutation, but it documents its association with BMAH and, additionally, papillary thyroid carcinoma and meningioma.
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Kim, Hyunhee, Ka Young Lim, Jin Woo Park, Jeongwan Kang, Jae Kyung Won, Kwanghoon Lee, Yumi Shim, et al. "Sporadic and Lynch syndrome-associated mismatch repair-deficient brain tumors." Laboratory Investigation 102, no. 2 (November 30, 2021): 160–71. http://dx.doi.org/10.1038/s41374-021-00694-3.
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AbstractMismatch repair-deficient (MMRD) brain tumors are rare among primary brain tumors and can be induced by germline or sporadic mutations. Here, we report 13 MMRD-associated (9 sporadic and 4 Lynch syndrome) primary brain tumors to determine clinicopathological and molecular characteristics and biological behavior. Our 13 MMRD brain tumors included glioblastoma (GBM) IDH-wildtype (n = 9) including 1 gliosarcoma, astrocytoma IDH-mutant WHO grade 4 (n = 2), diffuse midline glioma (DMG) H3 K27M-mutant (n = 1), and pleomorphic xanthoastrocytoma (PXA) (n = 1). Next-generation sequencing using a brain tumor-targeted gene panel, microsatellite instability (MSI) testing, Sanger sequencing for germline MMR gene mutation, immunohistochemistry of MMR proteins, and clinicopathological and survival analysis were performed. There were many accompanying mutations, suggesting a high tumor mutational burden (TMB) in 77%, but TMB was absent in one case of GBM, IDH-wildtype, DMG, and PXA, respectively. MSH2, MLH1, MSH6, and PMS2 mutations were found in 31%, 31%, 31% and 7% of patients, respectively. MSI-high and MSI-low were found in 50% and 8% of these gliomas, respectively and 34% was MSI-stable. All Lynch syndrome-associated GBMs had MSI-high. In addition, 77% (10/13) had histopathologically multinucleated giant cells. The progression-free survival tended to be poorer than the patients with no MMRD gliomas, but the number and follow-up duration of our patients were insufficient to get statistical significance. In the present study, we found that the most common MMRD primary brain tumor was GBM IDH-wildtype. The genetic profile of MMRD GBM was different from that of conventional GBM. MMRD gliomas with TMB and MSI-H may be sensitive to immunotherapy but resistant to temozolomide. Our findings can help develop better treatment options.