Academic literature on the topic 'Common and rare germline mutations'
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Journal articles on the topic "Common and rare germline mutations"
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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.
Dissertations / Theses on the topic "Common and rare germline mutations"
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Donati, B. "IDENTIFICATION OF RARE AND COMMON GENETIC VARIANTS ASSOCIATED WITH HEPATOCELLULAR CARCINOMA IN PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE: MECHANISMS AND CLINICAL IMPLICATIONS." Doctoral thesis, Università degli Studi di Milano, 2017. http://hdl.handle.net/2434/493452.
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Nonalcoholic fatty liver disease (NAFLD) affects roughly 30% of the general population and its prevalence is increasing worldwide, in particular in Western countries where it is projected to become the main cause of hepatocellular carcinoma (HCC) within 2025. Although the majority of NAFLD progressing towards HCC are individuals with advanced fibrosis, NAFLD-HCC frequently develops even in patients without cirrhosis. Family history and genetic factors play an important role in the pathogenesis of progressive NAFLD and of HCC. Our hypothesis is that both common and rare variants may have a role in influencing HCC predisposition.
Aim of this study was (1) to evaluate whether the rs641738 C>T common genetic variant in the MBOAT7/TMC4 locus, the last genetic variant recently associated with NAFLD development and progression towards early phases of damage, also predisposes to HCC in patients stratified by the presence of severe fibrosis, and (2) to assess whether telomere attrition and inherited rare hTERT mutations associates with NAFLD-HCC development, since mutations in Telomerase gene have been linked to familial liver diseases.
In the first part of the study, we found that the rs641738 T allele is associated with NAFLD-HCC independently of fibrosis severity and of several confounders (allelic OR 1.65, 95% confidence interval 1.08-2.55; n=765), particularly in patients without advanced fibrosis (p<0.001). The rs641738 risk T allele is associated with reduced MBOAT7 expression, evaluated by qRT-PCR on liver biopsy, specifically in patients without severe fibrosis, and was more strongly associated with HCC development in this specific subgroup (p=0.02). Moreover, the number of PNPLA3, TM6SF2, and MBOAT7 risk alleles is associated with NAFLD-HCC development independently of clinical factors (p<0.001), but it did not significantly improve their predictive accuracy. The independent association between the
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MBOAT7 risk variant and increased HCC risk has also been confirmed in a combined cohort of chronic hepatitis C or alcoholic liver disease patients without cirrhosis (n=1121).
In the second part of the study, we found that telomere length, evaluated by qRT-PCR, is progressively reduced in 40 NAFLD-HCC vs. 45 NAFLD-cirrhosis (p=0.048) and 64 healthy controls (p=0.0006), independently of age and sex. We detected an enrichment of rare germline coding mutations in hTERT in NAFLD-HCC patients vs. controls, even after considering 78 European primary liver cancers. No mutations were found in NAFLD-cirrhosis and local controls, and only one in 503 Europeans from the 1000Genomes Project. Thus, overall mutations frequency was 0.025 in cases vs. <0.001 in controls (p=0.0005 at Burden test). hTERT mutations occurred predominantly in females (p=0.03) and were predominantly located in the N-terminal template-binding domain of the gene (p=0.037 for specific enrichment). The frameshift Glu113Argfs*79 and the missense Glu668Asp damaging mutations co-segregated with liver disease in families. Besides Glu668Asp, the Ala67Val variant resulted in reduced intracellular protein levels in HEK-293 cells. These data suggest that telomere attrition and certain hTERT mutations are involved in the pathogenesis of NAFLD-HCC.
In conclusion, the identification of new common prognostic marker, such as the MBOAT7 rs641738 variant, in NAFLD patients and the evaluation of hTERT rare mutations in NAFLD-HCC may improve HCC screening strategies, by assisting in the identification of subjects at risk even in the absence of severe fibrosis and of family members at high risk of progressive liver disease, respectively. In future, functional studies are needed in order to understand the exact role and the interplay of the several common and rare genetic variants which contribute to the molecular mechanisms that underlie the pathogenesis of NAFLD-HCC.
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Garg, Sumedha. "Role of two genes, CACNA1D and CADM1, with common or rare mutations in aldosterone producing adenomas of the adrenal." Thesis, University of Cambridge, 2019. https://www.repository.cam.ac.uk/handle/1810/289390.
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Primary aldosteronism (PA) accounts for 5-10% of all hypertension. One of the major causes of PA is sporadic formation of aldosterone-producing adenomas (APAs). These benign tumours develop in the cortical region of adrenal glands and autonomously secrete excessive amounts of aldosterone. This hormone increases sodium retention and water reabsorption by the kidneys, leading to high blood pressure. Landmark discoveries of somatic mutations in APAs led to better understanding of molecular mechanisms causing autonomous aldosterone secretion. The first mutations were found in KCNJ5, followed by ATP1A1, ATP2B3 and CACNA1D, all encoding cation-channels or transporters. Several in vitro studies showed disruption of cellular ion-balance leading to the phenotype of hyper-aldosterone secretion from APAs. Following our lab's discovery of initial four somatic mutations by whole exome sequencing, over 30 single-base change mutations have been reported in the CACNA1D gene, which encodes the a1 subunit of an L-type Ca2+ channel (LTCC), CaV1.3. Initial and several subsequent mutations cause electrophysiological gain-of-function with increased activation and/or slowed inactivation of CaV1.3. Prior to the discovery of these mutations, L-type Ca2+ channels were not considered important in regulation of aldosterone production. In the first part of my thesis, I investigated two of the mutations and showed that the gain-of-function results in increased aldosterone secretion from an adrenocortical carcinoma cell line, H295R, when transiently transfected with the mutants. I also showed that CaV1.3 can play a role in physiological aldosterone secretion, finding that CYP11B2 expression is reduced by 50% in the adrenals of CaV1.3 knockout mice. The discovery of mutations in CACNA1D led to a drug discovery challenge award from a pharmaceutical company in which high-throughput screening of CaV1.3-expressing cells was undertaken against the company's 1.8M compound library. I identified the adrenal isoforms of the channel's alpha and beta subunits (CACNA1D and CACNB2), and helped development of the stable HEK293 cell line used for screening. This led to 3 tool compounds (A, B & C) that were selective antagonists for CaV1.3 over another family member of the ion channels in high-throughput electrophysiological experiments using IonWorks Barracuda and QPatch platforms. I showed compound B to effectively inhibit aldosterone secretion in both H295R and primary adrenal cells isolated from a normal adrenal. This finding is a significant step in developing compound B further into a CaV1.3-selective drug for treating PA patients without cardiovascular side effects as in the case of existing dihydropyridine class of Ca2+ channel blockers. The second part of my thesis focused on genotyping and whole exome sequencing of 59 APAs from 52 patients, in order to identify further genes underlying primary aldosteronism. Mutations in previously reported genes were identified in 34 of the APAs (57.6%). CACNA1D was the most commonly mutated gene (20.3%) in this cohort, but not KCNJ5 (16.9%) as previously reported. This variation in the frequencies observed is perhaps due to the different methods used for screening PA. For example, many of our patients were detected by renin measurement in resistant hypertension, and their APA identified by a unique PET-CT (using C11 metomidate), in place of adrenal vein sampling. In addition to this, novel somatic mutation was found in a gene not encoding an ion channel, however, this protein was previously linked to cell-cell adhesion and tumour suppression. The gene identified is CADM1, a cell adhesion molecule 1, and the mutation found leads to substitution of uncharged by negatively charged amino acid in the single transmembrane domain of this cell surface protein. The likely significance of this discovery was greatly enhanced when we ascertained that one of the 'private' somatic mutations found on whole exome sequencing of APAs in Munich was in fact a similar substitution in the adjacent amino acid of the membrane-spanning domain. High expression of CADM1 in zona glomerulosa (ZG) was found, the site of aldosterone synthesis in the adrenal cortex and in the APAs, as well as the aldosterone producing cell clusters (APCCs) within the ZG. In vitro experiments using H295R cells showed both mutations in CADM1 lead to 10-20 fold upregulation of CYP11B2 transcription, on qPCR, resulting in 2-4-fold increase of aldosterone secretion, compared to the wild-type CADM1. Despite the introduction of a negative charge into the transmembrane domain, both mutants could translocate to the cell surface. The evidence to date, points to the loss of cell-cell adhesion in the presence of mutant CADM1 as the cause of uncontrolled aldosterone synthesis. Silencing of CADM1 in H295R cells revealed downregulation of aldosterone synthesis and secretion. Transcriptome analysis by RNAseq, of H295R cells expressing wild-type or mutant CADM1 or silenced CADM1 showed a large number of differentially expressed genes. Mutant CADM1 upregulated genes involved in steroidogenesis and ACTH response pathways. A possible role of CADM1 was found to be in the regulation of inter-cell communication via gap junction protein, connexin-43 (Cx43). This was upregulated with higher expression on plasma membrane in the CADM1 silenced cells. TSG101, a protein involved in lysosomal degradation of Cx43 was downregulated in the absence of CADM1 and possibly the mechanism for increased Cx43 expression. Also, immunostaining of adrenal sections showed internalised para-nuclear staining localisation of Cx43 in the ZG, APAs and APCCs, regions with high CADM1 expression compared to membranous localisation of Cx43 in ZF. In contrast to the common and numerous mutations in CACNA1D, mutations in CADM1 are rare. Nonetheless, they may enhance our understanding of the functional significance of glomerular structure of the outer zone of adrenal cortex, where cell-cell adhesion and intercellular communication appear critical for the regulation of aldosterone secretion.
Books on the topic "Common and rare germline mutations"
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Suman, Shankar, Shivam Priya, and Akanksha Nigam, eds. Breast Cancer: Current Trends in Molecular Research. BENTHAM SCIENCE PUBLISHERS, 2022. http://dx.doi.org/10.2174/97816810895221120101.
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Breast cancer is one of the most common cancer types worldwide, and is a leading cause of cancer related deaths in women. In this book, medical experts review our current understanding of the molecular biology and characteristics of breast cancer. The topics covered in this book provide comprehensive knowledge of mechanisms underlying breast carcinogenesis, and are intended for a wide audience including scientists, teachers, and students. 11 chapters present information about several topics on breast cancer, including the role of cell growth and proliferation pathways, androgen and cytokine signaling, germline mutations in breast cancer susceptibility genes, and molecular factors causing invasive and metastatic breast cancer. In addition, the editors discuss the recent advancements in multi-omics data analysis based on inter-and intra-tumor molecular profiles. The reference highlights how the knowledge and understanding of the biological behavior of breast neoplasms have facilitated ongoing investigations into dietary polyphenolic compounds with antioxidant properties, making them function as cancer chemopreventive agents. Along with this, the current development of treatment strategies such as targeted molecular therapy, and radiation therapy is brought to the fore to update readers.
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Penney, Kathryn L., Kyriaki Michailidou, Deanna Alexis Carere, Chenan Zhang, Brandon Pierce, Sara Lindström, and Peter Kraft. Genetic Epidemiology of Cancer. Oxford University Press, 2017. http://dx.doi.org/10.1093/oso/9780190238667.003.0005.
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Chapter 5 reviews epidemiologic studies conducted to identify germline (inherited) susceptibility loci. These studies can involve associations observed within high-risk family pedigrees or in large studies of unrelated individuals. The chapter reviews the methods used to estimate the aggregate contribution of inherited genetic susceptibility and to identify specific genetic loci associated with risk. Although there is considerable variability across cancers, most cancers exhibit familial clustering, driven in part by a small number of known rare variants with large relative risks and a larger number of common variants with modest relative risks. The chapter discusses the implications of these findings for clinical care, public health, and tumor biology. It closes with a discussion of open questions, most notably the puzzle of “missing heritability”: the fact that—despite tremendous advances—multiple lines of evidence suggest that most specific risk variants, both rare and common, have yet to be discovered.
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Harms, Matthew B., and Timothy M. Miller. Amyotrophic Lateral Sclerosis. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199937837.003.0027.
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Recent advances in sequencing technologies have dramatically expanded the number of genes associated with amyotrophic lateral sclerosis, including rare but highly penetrant causative mutations as well as common risk alleles. This chapter discusses these gene discoveries and how they have implicated a diverse array of biological pathways essential for motor neuron health and have begun to inform our understanding of ALS pathogenesis as a heterogeneous and multistep process. Insights from these discoveries are leading to a new generation of targeted therapies directed at specific genes and are poised to inform how patients with amyotrophic lateral sclerosis are evaluated and treated in the clinic.
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Marini, Carla, and Renzo Guerrini. Biological Basis of Primary Generalized Epilepsies—Genetics. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199937837.003.0036.
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Primary generalized epilepsies account for 30% of all epilepsies. These age-related epilepsies without structural brain lesions and normal development have a high heritability. Based on the main seizure type and their age of onset, four main subsyndromes are recognized. Rare autosomal dominant families carry mutations in a few genes involved in ion channel functions, whereas common genes are yet to be discovered. The complex inheritance involving multiple genes is the major limiting factor preventing to uncover their genetic architecture. Understanding genetic determinants is the key to unraveling the neurobiology and to improve therapies for these disorders.
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Sheppard, Mary N. Myocardial non-compaction. Edited by José Maria Pérez-Pomares, Robert G. Kelly, Maurice van den Hoff, José Luis de la Pompa, David Sedmera, Cristina Basso, and Deborah Henderson. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198757269.003.0026.
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Isolated left ventricular non-compaction is a controversial entity which has only been reported in the past 30 years. It is becoming more frequently diagnosed due to the use of echocardiography and MRI. It can present in fetal life, infancy, childhood, and adult life. Clinically, the patient can present with cardiac arrhythmias, cardiac failure, systemic emboli due to thrombosis within the ventricles, and sudden death. It can be a genetic entity associated with mutations in many genes associated with hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic cardiomyopathy. It is a rare entity found at autopsy and is more common in children than adults. In the past the prognosis has been considered worse in children then in adults. Treatment is usually empirical, dealing with the cardiac failure, arrhythmias, and thromboemboli.
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Wackerhage, Henning, Jonathon Smith, and Darren Wisniewski. Molecular exercise physiology. Edited by Neil Armstrong and Willem van Mechelen. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780198757672.003.0031.
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Molecular exercise physiology is the study of exercise physiology using molecular biology methods. The development of differentiated cell types is regulated by transcription factors like the muscle-making MyoD that specifies cell type, while others regulate the development of muscle, tendons, and bones. Maternal nutrition and exercise commonly affect embryonic development through epigenetic mechanisms. Adaptation to exercise involves sensor proteins detecting exercise-related signals, the processing of signals by signalling proteins and networks, and the regulation of the actual adaptations by effector proteins. Many sport- and exercise-related traits depend on both common and rare DNA sequence variations, including the muscle mass-increasing myostatin (GDF8) loss-of-function and the haematocrit-increasing EPOR gain-of-function mutations. Additionally, common DNA sequence variations contribute to the inherited variability of development, body height, strength, and endurance. Finally, in addition to ethical concerns, current genetic performance tests only explain a fraction of the variation of sport and exercise-related traits.
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Tangen, Catherine M., Marian L. Neuhouser, and Janet L. Stanford. Prostate Cancer. Oxford University Press, 2017. http://dx.doi.org/10.1093/oso/9780190238667.003.0053.
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Prostate cancer is the most common solid tumor and the second leading cause of cancer-related mortality in American men. Worldwide, prostate cancer ranks second and fifth as a cause of cancer and cancer deaths, respectively. Despite the international burden of disease due to prostate cancer, its etiology is unclear in most cases. Established risk factors include age, race/ancestry, and family history of the disease. Prostate cancer has a strong heritable component, and genome-wide association studies have identified over 110 common risk-associated genetic variants. Family-based sequencing studies have also found rare mutations (e.g., HOXB13) that contribute to prostate cancer susceptibility. Numerous environmental and lifestyle factors (e.g., obesity, diet) have been examined in relation to prostate cancer incidence, but few modifiable exposures have been consistently associated with risk. Some of the variability in results may be related to etiological heterogeneity, with different causes underlying the development of distinct disease subgroups.
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Levtchenko, Elena N., and Mirian C. Janssen. Cystinosis. Edited by Neil Turner. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780199592548.003.0339_update_001.
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Cystinosis is a rare autosomal recessive disease caused by mutations in the lysosomal cystine transporter cystinosin encoded by the CTNS gene (17p.13.2). Cystinosis is characterized by lysosomal cystine accumulation throughout the body with renal Fanconi syndrome being the most common presenting symptom of a multisystem disorder. It must be distinguished from cystinuria in which formation of cystine stones is the core problem. When left untreated, kidney dysfunction gradually progresses towards end-stage renal failure during the first 10 years of life. The advent of renal replacement therapy allowed cystinosis patients to survive into adulthood, but revealed numerous extrarenal manifestations of the disease, affecting eyes, endocrine organs, gastrointestinal tract, muscles, and central and peripheral nervous systems. The disease mechanism of cystinosis is not fully understood. The administration of the cystine-depleting agent cysteamine slows down renal and extrarenal organ damage, pointing to the pivotal role of cystine accumulation in the disease pathogenesis. Treatment with cysteamine should be initiated as early as possible and continued lifelong, and also after kidney transplantation for protecting extrarenal organs. Cysteamine eye drops are an indispensable part of the treatment of corneal cystine accumulation. Life expectancy of cystinosis patients has substantially improved and is now above 50 years.
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Foggensteiner, Lukas, and Philip Beales. Bardet–Biedl syndrome and other ciliopathies. Edited by Neil Turner. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0314.
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Ciliopathies encompass a genotypically complex and phenotypically variable and overlapping series of disorders that makes the general term ‘ciliopathies’ very useful. The genes behind these conditions encode parts of the machinery of the primary cilium. This is also true of the major cystic kidney disorders autosomal dominant polycystic kidney disease and autosomal recessive polycystic kidney disease, but the ‘long tails’ of other ciliopathies are characterized by variable nephropathy (often without cyst formation), retinopathy, and effects on brain and skeletal development. Not all have substantial renal phenotypes. Bardet–Biedl syndrome (BBS) is an autosomal dominant condition characterized by obesity, retinopathy, nephropathy, and learning difficulty, but renal abnormalities are varied and end-stage renal failure occurs in only a minority. Many BBS genes have been described. Alström syndrome is a rare recessive disorder again associated with obesity and retinopathy, but also deafness and dilated cardiomyopathy. Renal failure is a common but later feature. Joubert syndrome is an autosomal dominant condition but can arise from mutations in at least 10 genes. It has a wide phenotypic variation with a common link being hypodysplasia of the cerebellar vermis and other abnormalities giving rise to the ‘molar tooth sign’ on cerebral magnetic resonance imaging scanning, associated with hypotonia in infancy, central ataxia, ocular apraxia, developmental delay, and varying degrees of cognitive impairment. Jeune syndrome is a recessive condition characterized by osteochondrodysplasia which can give rise to hypodevelopment of the chest wall known as suffocating thoracic dystrophy, in addition to other manifestations.
Book chapters on the topic "Common and rare germline mutations"
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Castaneda, Carlos A. "Molecular and Cellular Analyses of Breast Cancers in Real Life." In Improving Oncology Worldwide, 75–82. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-030-96053-7_10.
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AbstractBreast cancer is the most common women’s malignancy. Incorporation of biomarkers of prognosis and prediction of response are needed to improve treatment management. Lectures for immunohistochemistry of estrogen, progesterone, and HER2 receptors as well as Ki67 staining in cancer cells have been incorporated, and their positive cutoffs have periodically been reviewed. Gene expression platforms in tumor lesions as well as germline and somatic mutations have also been included in the practice for treatment selection. Liquid biopsy evaluating circulating tumor cells (CTCs) and circulating DNA can also predict survival and has reached the clinical practice, although it needs better standardization. On the other side, biomarkers can also evaluate stroma cells in the tumor microenvironment, and they can predict survival and response to chemotherapy and targeted treatment. They have been incorporated in the daily practice, and new methodologies for obtaining more information are currently being developed.
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Eeles, Rosalind A. "The genetics of inherited cancers." In Oxford Textbook of Medicine, edited by Tim Eisen, 456–70. Oxford University Press, 2020. http://dx.doi.org/10.1093/med/9780198746690.003.0047.
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All cancer can be termed ‘genetic’ as the disease is caused by somatic cell mutations (alterations in the DNA code), which result in abnormal cellular growth and/or proliferation. Most of these mutations are sporadic (only occurring in the cancer cell), but some are due to the inheritance of a germline mutation in a cancer predisposition gene. Cancer predisposition genes can be rare and confer a high cancer risk (about 10-fold lifetime relative risk), or common and confer a low to moderately increased risk (from just over onefold, up to two- to threefold). They have been shown to be involved in causing some of most common cancers as well as some rare cancers. Cancer genetics will become part of mainstream clinical pathways for cancer care in the coming years and is likely to contribute to healthcare that is tailored to individual patients.
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Boelaert, Kristien, and Anthony P. Weetman. "Thyroid cancer." In Oxford Textbook of Medicine, edited by Mark Gurnell, 2302–12. Oxford University Press, 2020. http://dx.doi.org/10.1093/med/9780198746690.003.0247.
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Thyroid cancers are the most common endocrine malignancies and their incidence is rising globally, largely due to significant increases in small, incidentally detected low-risk tumours. Follicular epithelial cell cancer is the commonest type; this usually presents with usually well differentiated tumours and has an excellent prognosis, but occasionally highly undifferentiated; it may be induced by exposure to ionizing radiation. Medullary thyroid carcinoma arises from parafollicular C cells; it comprises 3–5% of all thyroid cancers; usually hereditary autosomal dominant forms associated with germline point mutations in the RET proto-oncogene. Rare thyroid tumours include anaplastic carcinomas, which present as a rapidly enlarging and fixed thyroid masses, sometimes with local pain; they are rapidly fatal; sarcomas; and primary lymphomas—these usually present as a rapidly enlarging thyroid mass in a patient with Hashimoto’s thyroiditis.
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Chantada, Guillermo, and Carlos Rodríguez-Galindo. "Retinoblastoma." In Oxford Textbook of Cancer in Children, 270–76. Oxford University Press, 2020. http://dx.doi.org/10.1093/med/9780198797210.003.0031.
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Retinoblastoma is the most common paediatric ocular malignancy. Its disease-free survival rate in developed countries is higher than 95%, but in the developing world this tumour presents with advanced disease leading to poorer outcome. Late diagnosis and problems with compliance for treatment affect the outcome in that setting. Retinoblastoma may occur in children with germline mutations of the RB1 gene, who usually present with bilateral heritable disease. In those with somatic mutations, it always presents as unilateral and non-hereditable disease. The former have a higher susceptibility for secondary malignancies occurring later in life. Enucleation of the affected eyeball is often curative when the disease presents intraocularly, but conservative therapies have evolved from conventional external photon-beam radiotherapy, which was associated with severe long-term toxicity, to chemotherapy plus local treatments. Recently, local intra-arterial and intravitreal chemotherapy has been more intensively used, leading to higher preservation rates.
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Matise, Michael P., and Alexandra L. Joyner. "Production of targeted embryonic stem cell clones." In Gene Targeting. Oxford University Press, 1999. http://dx.doi.org/10.1093/oso/9780199637928.003.0007.
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The discovery that cloned DNA introduced into tissue culture cells can undergo homologous recombination at specific chromosomal loci has revolutionized our ability to study gene function in cell culture and in vivo. In theory, this technique, termed gene targeting, allows one to generate any type of mutation in any cloned gene. The kinds of mutations that can be created include null mutations, point mutations, deletions of specific functional domains, exchanges of functional domains from related genes, and gain-of-function mutations in which exogenous cDNA sequences are inserted adjacent to endogenous regulatory sequences. In principle, such specific genetic alterations can be made in any cell line growing in culture. However, not all cell types can be maintained in culture under the conditions necessary for transfection and selection. Over ten years ago, pluripotent embryonic stem (ES) cells derived from the inner cell mass (ICM) of mouse blastocyst stage embryos were isolated and conditions defined for their propogation and maintenance in culture (1, 2). ES cells resemble ICM cells in many respects, including their ability to contribute to all embryonic tissues in chimeric mice. Using stringent culture conditions, the embryonic developmental potential of ES cells can be maintained following genetic manipulations and after many passages in vitro. Furthermore, permanent mouse lines carrying genetic alterations introduced into ES cells can be obtained by transmitting the mutation through the germline by generating ES cell chimeras (described in Chapters 4 and 5). Thus, applying gene targeting technology to ES cells in culture affords researchers the opportunity to modify endogenous genes and study their function in vivo. In initial studies, one of the main challenges of gene targeting was to distinguish the rare homologous recombination events from more commonly occurring random integrations (discussed in Chapter 1). However, advances in cell culture and in selection schemes, in vector construction using isogenic DNA, and in the application of rapid screening procedures have made it possible to identify homologous recombination events efficiently. Since there are numerous publications available that describe basic tissue culture techniques in this chapter we will only describe techniques specific for ES cells.
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Biesecker, Leslie G. "Proteus Syndrome." In Overgrowth Syndromes, 199–216. Oxford University Press, 2019. http://dx.doi.org/10.1093/med/9780190944896.003.0011.
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Proteus syndrome is an exceedingly rare disorder, perhaps the least common of all overgrowth syndromes but one of the most distinctive because of its segmental nature and unrelenting progression. Proteus syndrome occurs sporadically and was the first of the segmental overgrowth syndromes found to be caused by somatic mosaicism. The discovery of an activating mutation in AKT1 by Les Biesecker and colleagues at the National Institutes of Health provided the initial molecular proof for somatic mosaicism in Proteus syndrome. Overgrowth in Proteus syndrome can involve nearly any tissue or part of the body. Presumably a germline mutation that would affect all tissues of the body would be lethal. Overgrowth of a tissue or a body part is the distinctive manifestation of Proteus syndrome but in most cases will be accompanied by other cutaneous, skeletal, vascular, or soft tissue findings. Although the possibility of an increased risk for developing neoplastic disease is a concern in any overgrowth disorder, this has not been demonstrated in Proteus syndrome.
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Gilbertson-Dahdal, Dorothy L. "Common Congenital Syndromes." In Musculoskeletal Imaging Volume 2, edited by Mihra S. Taljanovic and Tyson S. Chadaz, 304–10. Oxford University Press, 2019. http://dx.doi.org/10.1093/med/9780190938178.003.0115.
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Chapter 114 focuses on several of the more commonly seen types of skeletal dysplasia, such as achondroplasia, Hurler syndrome, osteogenesis imperfecta, and thanatophoric dwarfism. Skeletal dysplasia results from genetic mutations that cause abnormalities in bone or cartilage. There are more than 450 skeletal dysplasias and most are rare. Many dysplasias are detected on prenatal US, and family history, physical examination, and molecular and genetic testing are also used in diagnosis. A skeletal survey is recommended including skull AP and lateral; thoracolumbar spine AP and lateral; and AP views of the chest, pelvis, upper limbs, and lower limbs. Treatment options and management vary.
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Maria Lider Burciulescu, Sofia, and Monica Livia Gheorghiu. "Advances in the Diagnosis and Treatment of Pheochromocytomas and Paragangliomas in the Era of Personalized Genetic Diagnostic." In Adrenal Glands - The Current Stage and New Perspectives of Diseases and Treatment [Working Title]. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.108298.
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Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that arise from chromaffin cells. Almost 40% of all PPGLs cases are caused by germline mutations and 30–60% have somatic mutations. The incidence of hereditary syndromes in apparently sporadic cases is as high as 35%. Currently, more than 20 susceptibility genes have been identified, including at least 12 distinct genetic syndromes, with particular clinical features and prognosis. In this chapter, we summarize recent advances in the management of PPGLs from clinical diagnosis to targeted molecular treatment, based on the genetic profile. Classically, patients with PPGLs were diagnosed by sign and symptoms, e.g., hypertension (with or without paroxysms) and headache. Nowadays, about half of PPGLs are diagnosed as incidentalomas or during the surveillance screening in patients with known mutations for PPGL susceptibility genes, familial syndromes, or with a previous PPGL; a high percent of these patients have normal blood pressure. Plasma or urinary fractionated metanephrines remain the major biochemical tests for confirmation. Functional imaging, with a radiopharmaceutical chosen according to the tumor genotype and biology, improves tumor detection (notably for metastases and multifocal tumors) and links to targeted radionuclide therapy. Detecting the germline and somatic mutations associated with PPGLs is a promising approach to understand the clinical behavior and prognosis and to optimize the management of these tumors.
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Yu, Yun, and Richard R.P.A. Crooijmans. "Genomics Underlying Familial Thyroid Carcinoma in Dogs." In Thyroid Cancer - The Road From Genes to Successful Treatment [Working Title]. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.108480.
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Thyroid cancer is the most common endocrine neoplasm occurring in dogs. We reported familial thyroid follicular cell carcinomas (FCCs) in 54 Dutch German longhaired pointer (GLP) dogs. We investigated the genetics of the FCC in these dogs, including the germline risk mutations and somatic driver mutations. We identified the germline risk factor locating in the TPO gene for these hereditary FCCs through a combination of genome-wide association study (GWAS) and homozygosity mapping analyses using SNP array genotype data and whole-genome sequencing data. We further investigated the somatic mutation landscape of these FCCs using high-depth whole-genome sequencing technology of the tumors. A recurrent missense mutation in the GNAS gene was identified as a very promising driver mutation. We validated this somatic mutation using Sanger sequencing and revealed a prevalence of 62.5% among thyroid tumors identified in the Dutch GLPs. In addition, we can also review the findings in genetics of other canine thyroid tumors in recent years.
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Roth, Jonathan, Rina Dvir, and Shlomi Constantini. "Choroid plexus tumours." In Oxford Textbook of Neurological Surgery, edited by Ramez W. Kirollos, Adel Helmy, Simon Thomson, and Peter J. A. Hutchinson, 403–10. Oxford University Press, 2019. http://dx.doi.org/10.1093/med/9780198746706.003.0034.
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Choroid plexus tumours (CPT) are relatively rare and include three pathological subtypes: papilloma (CPP) (benign); carcinoma (CPC) (malignant); atypical papilloma (ACPP) (intermediate). Most cases of CPT occur during early childhood and infancy; however, occurrence at all paediatric ages as well as adulthood has been documented. The main treatment of CPT is surgical, aiming for complete resection in all subtypes of CPT. The location and vascularity of CPT present a special surgical challenge. Surgical excision of CPP can be curative. In the malignant CPC form, adjuvant chemotherapy is indicated. The role of radiotherapy is controversial. A subset of patients with CPT harbour germline or somatic TP53 mutations characterized by greater tumour aggressiveness and decreased survival.
Conference papers on the topic "Common and rare germline mutations"
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Ramos, Pilar, Anthony Karnezis, David Craig, Aleksandar Sekulic, Megan Russell, William Hendricks, Michael Barrett, et al. "Abstract LB-202: The rare, highly malignant small cell carcinoma of the ovary displays common inactivating germline and somatic mutations in the tumor suppressor SMARCA4." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-lb-202.
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Feijão, Maria Clara Tomaz, Fernanda Pimentel Arraes Maia, Mateus Coelho Gondim de Oliveira Lima, Vitória Moreira Soares, and Luiz Gonzaga Porto Pinheiro. "CONCERNING A FAMILY WITH BRCA2 MUTATION." In XXIV Congresso Brasileiro de Mastologia. Mastology, 2022. http://dx.doi.org/10.29289/259453942022v32s1019.
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Introduction: Breast cancer is the most common malignancy in women and represents a major obstacle to public health worldwide. The molecular diagnosis of this type of cancer is one of the main contemporary challenges in oncology, since it is hampered by a complex inheritance pattern, characterized by both genetic and environmental factors. Only a minority of breast cancers are explained by the presence of high penetrance gene mutations, such as those in the BRCA1 and BRCA2 genes, which together with mutations in intermediate penetrance genes explain only up to 25% of the risk. In fact, much of the genetic influence is elucidated by low penetrance variants. Mutations in the germline BRCA1 and BRCA2 are the most common alterations in cases of early onset or of family history of breast cancer. It is also important to acknowledge that BRCA2 mutations can increase the risk of developing other cancers. Some studies show a relation between BRCA2 mutations and the development of leukemia, especially acute myeloid leukemia (AML). Also, some of these mutations, when inherited from both parents, cause a rare form of Fanconi anemia, a syndrome associated with the development of AML. In addition, there are studies evaluating a higher risk of pancreatic and esophageal cancer in carriers of BRCA2 mutations. The risk of colorectal cancer is also increased in patients with BRCA1 mutations. However, there are also some authors who defend that BRCA2 mutations could also be related. The specific statistics are not well defined because of the lack of data focusing on the relationship with the aforecited types of cancers, demonstrating the need for further analysis. This study aims to report the case of a woman with breast cancer at an early age. Such malignancy is associated and was somehow induced by the rich family history, represented by the high prevalence of cancer in the ancestry. We report a 34-year-old woman with an extensive history of carcinoma in the family, who was diagnosed with breast cancer in July 2016. In order to confirm the diagnosis, it was required an ultrasound, which resulted in a 2.2×1.5 cm node on the right breast’s left superior quadrant, classified as BIRADS 4A. It also performed an ultrasound-guided biopsy that showed a tubular carcinoma on the right breast with the following characteristics: positive for estrogen and progesterone receptor, positive for KI 67 (5%), and negative for HER2, with staging of T1cN0M0. During anamnesis, the patient mentioned menarche at 12 years old, history of birth control pills use for 10 years, no pregnancy, and no breastfeeding. When it comes to family history, a great number of relatives were previously diagnosed with some type of cancer. Her paternal grandfather had rectum cancer at 42 years old and breast cancer at 62 years old. The paternal grandmother passed away because of a fast-progression leukemia at the age of 68. It is important to mention that her progenitors were first cousins. Furthermore, the patient’s dad was diagnosed with breast cancer at 62 years, alongside his three brothers who were also diagnosed with cancer: one with prostatic cancer at the age of 64 years and the other two with intestinal cancer at the ages of 64 and 68 years old. Considering such a family history, a genetic panel was performed, analyzing the genes related to hereditary cancer risk, and it identified mutations in the patient’s BRCA2 gene. Then, firstly, she performed a bilateral mastectomy in January 2017 with sentinel lymph node investigation, which was negative for neoplastic cells in the lymph nodes. Later, considering the BRCA2 mutation, in August 2017, the patient had to undergo prophylactic surgery: oophorectomy with salpingectomy.
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Babadi, Mehrtash, Samuel K. Lee, Andrey Smirnov, Lee Lichtenstein, Laura D. Gauthier, Daniel P. Howrigan, and Timothy Poterba. "Abstract 2287: Precise common and rare germline CNV calling with GATK." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-2287.
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Ko, Josephine Mun Yee, Lu wen Ni, Sheyne, Sta Ana Choi, Lisa Chan Lei, Li Dong Wang, and Maria Li Lung. "Abstract 5234: Rare deleterious germline mutations of candidate genes associated with risk of familial esophageal squamous cell carcinoma (ESCC) by targeted sequencing." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-5234.
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Souto, Emília Correia, Carolina Maria Marin, Gustavo Carvalho Costa, Igor Braga Farias, Bruno de Mattos Lombardi Badia, Icaro França Navarro Pinto, Roberta Ismael Lacerda Machado, Paulo Victor Sgobbi de Souza, Wladimir Bocca Vieira de Rezende Pinto, and Acary Souza Bulle Oliveira. "Family with atypical Parkinsonism due to CHCHD10 gene mutation." In XIII Congresso Paulista de Neurologia. Zeppelini Editorial e Comunicação, 2021. http://dx.doi.org/10.5327/1516-3180.502.
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Introduction: Parkinson’s disease - PD is the second most common agerelated neurodegenerative disorder. Characterized by a variety of motor and non-motor symptoms that relate to the loss of dopaminergic neurons in the midbrain black substance. Although most cases of PD are sporadic, 5–10% of patients have monogenetic mutations with a description of more than 20 genes for the familial form. Mitochondrial mutation in CHCHD10 has also been reported to be associated with a wide spectrum of neurodegenerative disorders, including PD. Objectives: Description of a rare recently described genetic cause of autosomal dominant parkinsonism. Methodology: Describe the case of a Brazilian woman with atypical parkinsonism due to CHCHD10 pathogenic variant that was followed up in our service. Result: Female, 64 years old. “. He started episodes of imbalance about 5 years ago, with falls, in addition to limb stiffness, worse on the left. 4 years ago, he started myalgia to great efforts with low subsequent tolerance to light effort. 1 year ago with urinary incontinence and choking past of poor performance in physical activities without pre-motor symptoms FAMILY: mother with clinical picture of possible dementia syndrome at age 60, history in the maternal family of myalgia, intolerance to physical exercise and hearing loss in adulthood. EXOMA: presence of variant c.146C > T (p.Ala49Val) in simple heterozygosity without CHCHD10 gene. MRI with thigh muscle hypotrophy in anterior and posterior thigh compartments; slight muscle edema in the legs. Conclusion: Pathogenic variants in the CHCHD10 gene should be considered in cases of atypical parkinsonism, especially in cases of positive familial history of mitochondrial myopathy or dementia.
Reports on the topic "Common and rare germline mutations"
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Chen, Zhuo. Screening for Novel Germline Rare Mutations Associated with Aggressive Prostate Cancer. Fort Belvoir, VA: Defense Technical Information Center, October 2014. http://dx.doi.org/10.21236/ada613447.
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