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1
Yun, Jiwon, Jung-Ah Kim, Byungjin Hwang, Hee Sue Park, Kyongok Im, Sung-Min Kim, Dajeong Jeong, Kyu Min Lim, Duhee Bang, and Dong Soon Lee. "Triple-Negative Myeloproliferative Neoplasms Vs. Calr, JAK2 or MPL-Mutated Myeloproliferative Neoplasms: Distinct Molecular Characteristics." Blood 132, Supplement 1 (November 29, 2018): 1772. http://dx.doi.org/10.1182/blood-2018-99-118013.
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Abstract Background: We compared the clinical, cytogenetic, molecular features, and telomere lengths of patients with triple negative MPN and MPN with any of CALR, JAK2 or MPL mutations. Methods: Target capture sequencing of 87 genes and molecular cytogenetic studies were performed in 61 Korean patients with MPN. Also, we searched the newly reported mutations and novel mutations in triple negative MPN [JAK2-G335D (germline), JAK2-F556V, JAK2-G571S (germline), JAK2-V625F (germline), MPL-T119I, MPL-S204F/P, MPL-E230G, MPL-V285E (germline), MPL-R321W (germline), MPL-Y591D, MPL-S505N and MPL-W515R]. We compared clinical and molecular characteristics between two groups. Additionally, we performed telomere quantitative FISH for 48 patients' samples and measured telomere/centromere ratios of them. Results: Among 61 patients, 13 patients showed mutations in CALR, 34 in JAK2, and 3 in MPL. All of JAK2 mutation and CALR mutation site were reported sites, but 2 among 5 mutation site of MPL were novel mutation [D128N, D261Y]. Twelve patients showed triple negative (7 of PMF 7, 2 of ET, and 3 of MPN-U) - they showed 8 different mutation sites among 6 different genes (ASXL1, DNMT3A, NPM1, POLG, SRSF2, and ZMYM3). NPM1, POLG, and ZMYM3 mutations were seen only in triple negative patients. NPM1 mutation was significantly higher in triple negative MPN (P=0.0301). In telomere length study, there was no statistical difference between triple negative group (T/C ratio mean 12.5) and CALR, JAK2 or MPL mutated group (T/C ratio mean 10.0). Although, MPN patients with telomere length shorter than normal control's lower 10% (7.04) showed poor prognosis (P=0.0045). Conclusions: Patients with triple negative MPN are characterized by high frequency of NPM1 mutation and less number of somatic mutations. Since the mutational analysis for diagnostic purposes is limited to exons 14 of JAK2, exon 10 of MPL and exon 9 of CALR at present, search for JAK2 and MPL mutations in other sites are essential in triple negative MPNs. Keywords: Myeloproliferative neoplasms, next-generation sequencing, triple negative MPN, chromosome, FISH, telomere Disclosures No relevant conflicts of interest to declare.
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Azaiez, Aïda, Éric F. Bouchard, Martine Jean, and François J. Belzile. "Length, orientation, and plant host influence the mutation frequency in microsatellites." Genome 49, no. 11 (November 2006): 1366–73. http://dx.doi.org/10.1139/g06-099.
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Microsatellites are simple, tandem DNA repeats that represent unstable regions of the genome. They undergo frequent changes in tract length by base additions or deletions due to DNA polymerase slippage during replication. To characterize factors affecting the frequency of spontaneous mutations occurring in microsatellites in plants, a reporter system was used in Arabidopsis thaliana and tomato ( Lycopersicon esculentum ). The β-glucuronidase (GUS) reporter system was used to measure the mutation frequency in various microsatellites (G7, G10, G13, G16, and C16) in somatic tissues. Our results indicate that this frequency increases with the number of repeats: a G16 tract was almost 80-fold more mutable than a G7 tract. Furthermore, the frequency of mutations depends on repeat orientation, as G16 was 3-fold more mutable than C16. The mutation rate was also found to differ markedly in Arabidopsis and tomato for an identical microsatellite. Indeed, Arabidopsis showed a 5-fold higher mutation frequency than tomato with the same G7 reporter construct. Finally, mutation in a G16 tract was frequent enough that mutations transmitted germinally to the next generation could be detected at a relatively high frequency.
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Whittaker, John C., Roger M. Harbord, Nicola Boxall, Ian Mackay, Gary Dawson, and Richard M. Sibly. "Likelihood-Based Estimation of Microsatellite Mutation Rates." Genetics 164, no. 2 (June 1, 2003): 781–87. http://dx.doi.org/10.1093/genetics/164.2.781.
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Abstract Microsatellites are widely used in genetic analyses, many of which require reliable estimates of microsatellite mutation rates, yet the factors determining mutation rates are uncertain. The most straightforward and conclusive method by which to study mutation is direct observation of allele transmissions in parent-child pairs, and studies of this type suggest a positive, possibly exponential, relationship between mutation rate and allele size, together with a bias toward length increase. Except for microsatellites on the Y chromosome, however, previous analyses have not made full use of available data and may have introduced bias: mutations have been identified only where child genotypes could not be generated by transmission from parents' genotypes, so that the probability that a mutation is detected depends on the distribution of allele lengths and varies with allele length. We introduce a likelihood-based approach that has two key advantages over existing methods. First, we can make formal comparisons between competing models of microsatellite evolution; second, we obtain asymptotically unbiased and efficient parameter estimates. Application to data composed of 118,866 parent-offspring transmissions of AC microsatellites supports the hypothesis that mutation rate increases exponentially with microsatellite length, with a suggestion that contractions become more likely than expansions as length increases. This would lead to a stationary distribution for allele length maintained by mutational balance. There is no evidence that contractions and expansions differ in their step size distributions.
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Birzu, C., A. Hillairet, M. Giry, N. Grandin, P. Verrelle, K. Mokhtari, Y. Marie, et al. "OS9.7 Telomere length, TERTp mutation and ALT status in adult diffuse gliomas." Neuro-Oncology 21, Supplement_3 (August 2019): iii19—iii20. http://dx.doi.org/10.1093/neuonc/noz126.065.
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Abstract BACKGROUND The current classification of adult diffuse gliomas integrates two alternative telomere maintenance mechanisms: reactivation of telomerase activity by TERT promoter (TERTp) mutations or ATRX mutations associated with alternative length telomere (ALT). We investigated here the relation between these two mechanisms, telomere length, and outcome in a large series of diffuse gliomas. MATERIAL AND METHODS We performed C-circle assay (CCA) to determine ALT status, determined telomere length in tumor (RTLt) and leukocyte (RTLl) in a cohort of 354 adult diffuse gliomas, and sequenced ATRX gene. We calculated an age-adjusted telomere score considering tumor and leukocyte (blood) telomere length and corrected by age. This score was used in univariate and multivariate survival analyses to evaluate the potential impact of telomere length on the prognosis of gliomas. We used the TCGA LGG-GBM dataset to validate our findings in an independent cohort. RESULTS RTLl and RTLt were associated with ATRX mutation and ALT phenotype, and negatively associated with age and TERTp mutations. ATRX mutations (found in 52% (64/123) of samples) were mostly transitions (C>T or T>C), and were associated with ALT phenotype. None of 1p/19q co-deleted oligodendrogliomas harbored an ALT phenotype. No patients with TERTp mutations had ALT phenotype except for a very small subgroup of patients (3/87, 3.4%) suggesting that multiple ways of telomere maintenance, may co-exist in a single tumor, probably expressed in different clones. Telomere age-adjusted score was independently associated with better outcome (HR= 0.73 [95% CI 0.56–0.97], p-value 0.03 adjusted for age, TERTp mutation, IDH mutation, 1p/19q co-deletion and WHO grade). These results were validated using the LGG-GBM TCGA dataset. CONCLUSION We unravel the relation between RTLl and RTLt, TERTp mutation and ALT phenotype and describe a novel telomere age-adjusted score independently associated with better prognosis in adult diffuse gliomas.
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Jiang, Xuejie, Changxin Yin, Junya Sun, Jiaying Cheng, Qiang Wang, Guopan Yu, Ling Jiang, et al. "Influence of FLT3-ITD Mutation and Length on the Treatment Response and Prognosis in Cytogenetically Normal AML Patients." Blood 132, Supplement 1 (November 29, 2018): 5245. http://dx.doi.org/10.1182/blood-2018-99-111063.
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Abstract BACKGROUND : Mutations of internal tandem duplication in FMS-like tyrosine kinase 3 (FLT3-ITD) contributed to poor prognosis in cytogenetically normal acute myeloid leukemia (CN-AML). FLT3 tyrosine kinase inhibitor sorafenib in combination with chemotherapy was applied to treat FLT3-ITD AML patients with limited efficacy. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was considered as a potent therapeutic regimen in FLT3-ITD patients, but additional sorafenib maintenance was indispensable to support their long-term survival after allo-HSCT. Studies showed that increasing ITD size may be accompanied with decreasing OS and RFS in AML patients, but it remained controversial about the prognostic implication of ITD mutant lengths, the prognostic influence was important to evaluate in determining the therapeutic strategy for AML patients with different ITD lengths. METHODS: Total 185 CN-AML patients with and without FLT3-ITD mutations were enrolled in this study. We retrospectively studied the clinical characteristic, treatment response, survival and relapse risk after chemotherapy or allo-HSCT plus sorafenib in these patients. Distribution of ITD lengths detected in AML patients suggested two groups including long (≥70bp) and short ITD length (<70bp). Influence of FLT3-ITD mutation and its length were investigated after chemotherapy or allo-HSCT plus sorafenib. RESULT: FLT3-ITD mutations were detected in 15 percentage of AML patients, and associated with leukocytosis, high blast percentage in bone morrow (BM) and increased risk of treatment failure. FLT3-ITD mutations indicated decreased complete remission (CR) rate, overall survival (OS) and relapse-free survival (RFS), and increased relapse risk (RR) in AML patients after chemotherapy plus sorafenib. Patients with long ITD length (≥70bp) had worse OS and RFS, and more relapse probability than these with short ITD length (< 0bp) or FLT3-WT, but patients with short ITD length and FLT3-WT had the similar RFS and RR after chemotherapy. Allo-HSCT plus sorafenib maintenance significantly prolonged OS and RFS, decreased RR in FLT3-ITD patients, especially in these with long ITD length instead of those with short ITD length. CONCLUSION: Our findings indicated that FLT3-ITD mutation and long ITD length had negative effect on treatment response and prognosis in CN-AML patients. Allo-HSCT plus sorafenib maintenance was an effective strategy to improve survival and decrease relapse probability, abrogated disadvantage from long ITD length in FLT3-ITD patients. Disclosures No relevant conflicts of interest to declare.
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Comeron, Josep M., and Martin Kreitman. "The Correlation Between Intron Length and Recombination in Drosophila: Dynamic Equilibrium Between Mutational and Selective Forces." Genetics 156, no. 3 (November 1, 2000): 1175–90. http://dx.doi.org/10.1093/genetics/156.3.1175.
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Abstract Intron length is negatively correlated with recombination in both Drosophila melanogaster and humans. This correlation is not likely to be the result of mutational processes alone: evolutionary analysis of intron length polymorphism in D. melanogaster reveals equivalent ratios of deletion to insertion in regions of high and low recombination. The polymorphism data do reveal, however, an excess of deletions relative to insertions (i.e., a deletion bias), with an overall deletion-to-insertion events ratio of 1.35. We propose two types of selection favoring longer intron lengths. First, the natural mutational bias toward deletion must be opposed by strong selection in very short introns to maintain the minimum intron length needed for the intron splicing reaction. Second, selection will favor insertions in introns that increase recombination between mutations under the influence of selection in adjacent exons. Mutations that increase recombination, even slightly, will be selectively favored because they reduce interference among selected mutations. Interference selection acting on intron length mutations must be very weak, as indicated by frequency spectrum analysis of Drosophila intron length polymorphism, making the equilibrium for intron length sensitive to changes in the recombinational environment and population size. One consequence of this sensitivity is that the advantage of longer introns is expected to decrease inversely with the rate of recombination, thus leading to a negative correlation between intron length and recombination rate. Also in accord with this model, intron length differs between closely related Drosophila species, with the longest variant present more often in D. melanogaster than in D. simulans. We suggest that the study of the proposed dynamic model, taking into account interference among selected sites, might shed light on many aspects of the comparative biology of genome sizes including the C value paradox.
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McDew-White, Marina, Xue Li, Standwell C. Nkhoma, Shalini Nair, Ian Cheeseman, and Tim J. C. Anderson. "Mode and Tempo of Microsatellite Length Change in a Malaria Parasite Mutation Accumulation Experiment." Genome Biology and Evolution 11, no. 7 (July 1, 2019): 1971–85. http://dx.doi.org/10.1093/gbe/evz140.
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Abstract Malaria parasites have small extremely AT-rich genomes: microsatellite repeats (1–9 bp) comprise 11% of the genome and genetic variation in natural populations is dominated by repeat changes in microsatellites rather than point mutations. This experiment was designed to quantify microsatellite mutation patterns in Plasmodium falciparum. We established 31 parasite cultures derived from a single parasite cell and maintained these for 114–267 days with frequent reductions to a single cell, so parasites accumulated mutations during ∼13,207 cell divisions. We Illumina sequenced the genomes of both progenitor and end-point mutation accumulation (MA) parasite lines in duplicate to validate stringent calling parameters. Microsatellite calls were 99.89% (GATK), 99.99% (freeBayes), and 99.96% (HipSTR) concordant in duplicate sequence runs from independent sequence libraries, whereas introduction of microsatellite mutations into the reference genome revealed a low false negative calling rate (0.68%). We observed 98 microsatellite mutations. We highlight several conclusions: microsatellite mutation rates (3.12 × 10−7 to 2.16 × 10−8/cell division) are associated with both repeat number and repeat motif like other organisms studied. However, 41% of changes resulted from loss or gain of more than one repeat: this was particularly true for long repeat arrays. Unlike other eukaryotes, we found no insertions or deletions that were not associated with repeats or homology regions. Overall, microsatellite mutation rates are among the lowest recorded and comparable to those in another AT-rich protozoan (Dictyostelium). However, a single infection (>1011 parasites) will still contain over 2.16 × 103 to 3.12 × 104 independent mutations at any single microsatellite locus.
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Savage, Sharon A., Neelam Giri, Gabriela M. Baerlocher, Nick Orr, Peter M. Lansdorp, and Blanche P. Alter. "TINF2, a Component of the Shelterin Telomere Protection Complex, Is Mutated in Dyskeratosis Congenita." Blood 110, no. 11 (November 16, 2007): 835. http://dx.doi.org/10.1182/blood.v110.11.835.835.
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Abstract Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized by the triad of abnormal nails, lacey reticular skin pigmentation, and oral leukoplakia. Patients with DC are at high risk of developing aplastic anemia, myelodysplastic syndrome and leukemia. Diagnosis of DC is challenging due to variability of the triad and heterogeneous clinical findings such as pulmonary and liver disease, avascular necrosis, esophageal or urethral stenosis and development delay. The unifying feature in DC is exceedingly short telomere lengths and defects in telomere biology. Gene mutations have been identified in DKC1 (X-linked), TERC and TERT (dominant, AD) and NOP10 (recessive), but approximately 60% of DC patients lack a known mutation. We identified a non-consanguineous family with AD DC and no mutations in DKCI, TERC or TERT. The first DC cases were monozygotic twin brothers (now deceased). Telomere length was determined by flow-FISH on the twins’ children (6 affected, 4 unaffected), wives, their 8 siblings and parents. Despite variable clinical phenotypes, the 6 affected individuals (1 female, 5 male) all had very short telomere lengths (<1st%ile for age). Unaffected relatives had normal telomere lengths. A single nucleotide polymorphism (SNP) genome-wide linkage screen (Human Linkage IVb, Illumina, Inc) was conducted using telomere length <1st%ile as the affected phenotype. SNPLINK was used to remove SNPs in linkage disequilibrium (D′=0.7, R2=0.4). Data were analyzed with GeneHunter under a parametric, AD, rare, highly-penetrant disease model. Evidence favoring linkage was found in a 17 megabase (Mb) region on chromosome 2p and a 3.1 Mb region on chromosome14q (LOD score=2.62 at both sites). Bi-directional sequence analysis of the two best candidate genes, DDX1 (2p) and TINF2 (14q) was conducted to identify mutations. A novel mutation, K280E, in TINF2 (protein name TIN2) was identified in the 6 living, affected family members but not in the 8 unaffected relatives, suggesting inheritance from the affected fathers. There were no mutations in DDX1. TINF2 was sequenced in 8 additional, unrelated DC probands without DKCI, TERC or TERT mutations and 7 with known mutations. An R282H mutation was present in 3 unrelated DC probands (1 Hoyeraal-Hreidarsson, 1 Revesz Syndrome). Another DC patient had an R282S mutation. TINF2 mutations were not present in unaffected relatives, DC probands with mutations in DKC1, TERC or TERT, or 298 controls. The mutation prevalence in DC probands represented in our cohort of patients with DC are DKC1 (18.8%), TERC (18.8%), TERT (6.2%), and TINF2 (31.2%). As a component of shelterin, the protein complex that stabilizes telomeres, TIN2 is highly evolutionarily conserved. It serves as a bridge between the three primary telomere DNA-binding proteins, TRF1, TRF2 and POT1 (via TPP1). In silico analyses predict that K280E, R282H and R282S are deleterious mutations. Functional studies are underway to characterize possible effects of these mutations on shelterin protein interactions. By focusing on telomere length as the affected phenotype, instead of the heterogeneous clinical features present in DC patients, we identified mutations in TINF2 and further validated telomere length as a diagnostic test for DC. This study demonstrates that TINF2 is the 5th gene mutated in DC, the 1st in Revesz Syndrome, and the 1st shelterin complex gene mutated in human disease.
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Du, Hong-Yan, Elena Pumbo, Jennifer Ivanovich, Ping An, Richard T. Maziarz, Ulrike M. Reiss, Deborah Chirnomas, et al. "TERC and TERT gene mutations in patients with bone marrow failure and the significance of telomere length measurements." Blood 113, no. 2 (January 8, 2009): 309–16. http://dx.doi.org/10.1182/blood-2008-07-166421.
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Abstract Dyskeratosis congenita (DC) is a rare inherited form of bone marrow failure (BMF) caused by mutations in telomere maintaining genes including TERC and TERT. Here we studied the prevalence of TERC and TERT gene mutations and of telomere shortening in an unselected population of patients with BMF at our medical center and in a selected group of patients referred from outside institutions. Less than 5% of patients with BMF had pathogenic mutations in TERC or TERT. In patients with BMF, pathogenic TERC or TERT gene mutations were invariably associated with marked telomere shortening (≪ 1st percentile) in peripheral blood mononuclear cells (PBMCs). In asymptomatic family members, however, telomere length was not a reliable predictor for the presence or absence of a TERC or TERT gene mutation. Telomere shortening was not pathognomonic of DC, as approximately 30% of patients with BMF due to other causes had PBMC telomere lengths at the 1st percentile or lower. We conclude that in the setting of BMF, measurement of telomere length is a sensitive but nonspecific screening method for DC. In the absence of BMF, telomere length measurements should be interpreted with caution.
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Shaver, Aaron C., and Paul D. Sniegowski. "Spontaneously Arising mutL Mutators in Evolving Escherichia coli Populations Are the Result of Changes in Repeat Length." Journal of Bacteriology 185, no. 20 (October 15, 2003): 6076–82. http://dx.doi.org/10.1128/jb.185.20.6076-6082.2003.
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ABSTRACT Over the course of thousands of generations of growth in a glucose-limited environment, 3 of 12 experimental populations of Escherichia coli spontaneously and independently evolved greatly increased mutation rates. In two of the populations, the mutations responsible for this increased mutation rate lie in the same region of the mismatch repair gene mutL. In this region, a 6-bp repeat is present in three copies in the gene of the wild-type ancestor of the experimental populations but is present in four copies in one of the experimental populations and two copies in the other. These in-frame mutations either add or delete the amino acid sequence LA in the MutL protein. We determined that the replacement of the wild-type sequence with either of these mutations was sufficient to increase the mutation rate of the wild-type strain to a level comparable to that of the mutator strains. Complementation of strains bearing the mutator mutations with wild-type copies of either mutL or the mismatch repair gene uvrD rescued the wild-type mutation rate. The position of the mutator mutations—in the region of MutL known as the ATP lid—suggests a possible deficiency in MutL's ATPase activity as the cause of the mutator phenotype. The similarity of the two mutator mutations (despite the independent evolutionary histories of the populations that gave rise to them) leads to a discussion of the potential adaptive role of DNA repeats.
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Norris, Kevin, Amanda J. Walne, Mark J. Ponsford, Kez Cleal, Julia W. Grimstead, Alicia Ellison, Jenna Alnajar, Inderjeet Dokal, Tom Vulliamy, and Duncan M. Baird. "High-throughput STELA provides a rapid test for the diagnosis of telomere biology disorders." Human Genetics 140, no. 6 (March 11, 2021): 945–55. http://dx.doi.org/10.1007/s00439-021-02257-4.
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AbstractTelomere biology disorders are complex clinical conditions that arise due to mutations in genes required for telomere maintenance. Telomere length has been utilised as part of the diagnostic work-up of patients with these diseases; here, we have tested the utility of high-throughput STELA (HT-STELA) for this purpose. HT-STELA was applied to a cohort of unaffected individuals (n = 171) and a retrospective cohort of mutation carriers (n = 172). HT-STELA displayed a low measurement error with inter- and intra-assay coefficient of variance of 2.3% and 1.8%, respectively. Whilst telomere length in unaffected individuals declined as a function of age, telomere length in mutation carriers appeared to increase due to a preponderance of shorter telomeres detected in younger individuals (< 20 years of age). These individuals were more severely affected, and age-adjusted telomere length differentials could be used to stratify the cohort for overall survival (Hazard Ratio = 5.6 (1.5–20.5); p < 0.0001). Telomere lengths of asymptomatic mutation carriers were shorter than controls (p < 0.0001), but longer than symptomatic mutation carriers (p < 0.0001) and telomere length heterogeneity was dependent on the diagnosis and mutational status. Our data show that the ability of HT-STELA to detect short telomere lengths, that are not readily detected with other methods, means it can provide powerful diagnostic discrimination and prognostic information. The rapid format, with a low measurement error, demonstrates that HT-STELA is a new high-quality laboratory test for the clinical diagnosis of an underlying telomeropathy.
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Aviv, Abraham, James J. Anderson, and Jerry W. Shay. "Mutations, Cancer and the Telomere Length Paradox." Trends in Cancer 3, no. 4 (April 2017): 253–58. http://dx.doi.org/10.1016/j.trecan.2017.02.005.
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Rokita, Jo Lynn, Krutika Gaonkar, Heba Ijaz, Daniel Miller, Tasso Karras, Mariarita Santi, Daniel Martinez, et al. "PATH-21. TELOMERE LENGTH ANALYSIS OF CNS TUMORS IN THE PEDIATRIC BRAIN TUMOR ATLAS." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii428. http://dx.doi.org/10.1093/neuonc/noaa222.656.
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Abstract Subsets of pediatric cancers, including high grade glioma (pHGG), have high rates of uniquely long telomeres, associated with ATRX gene mutations and alternative lengthening of telomeres (ALT). Ultimately, these cancers may benefit from a therapy stratification approach. In order to identify and further characterize pediatric brain tumors with telomere lengthening (TL), we determined the intratelomeric content in silico from paired WGS of 918 tumors from CBTTC Pediatric Brain Tumor Atlas (PBTA). The results were highly concordant with experimental assays to determine ALT in a subset of 45 pHGG tumors from the set. Overall, 13% of the PBTA cohort had telomere lengthening. We confirmed the highest rate of TL (37%) in the pHGG cohort (37/100 tumors; 30/82 patients). There was no statistical difference in age, gender or survival in subset analysis. As expected, the patient pHGG tumors with telomere lengthening were enriched for ATRX mutations (60%, q= 1.76e-3). However, 6 tumors without ATRX mutation also had normal protein expression, suggesting a different mechanism of inactivation or TL. The pHGG tumors with telomere lengthening had increased mutational burden (q=8.98e-3) and included all known pHGG cases (n=6) in the cohort with replication repair deficiencies. Of interest, the second highest rate of telomere lengthening was 9 subjects (24%) in the craniopharyngioma cohort. None of the craniopharyngioma tumors had ATRX mutations or low ATRX expression, and 55% of those with TL had CTNNB1 mutations. Finally, lower rates of telomere lengthening were found in medulloblastoma (10%), ependymoma (10%), low grade astrocytoma (8%) and ganglioglioma (7/47, 15%).
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Artzt, Karen, Janice Cookingham, and Dorothea Bennett. "A New Mutation (t-int) Interacts With the Mutations of the Mouse T/t Complex That Affect the Tail." Genetics 116, no. 4 (August 1, 1987): 601–5. http://dx.doi.org/10.1093/genetics/116.4.601.
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ABSTRACT A new recessive mutation affecting tail length is described. It is unlinked to the T/t-complex on chromosome 17 and yet it shows cumulative phenotypic effects with several t-complex mutations: T, TCu, tct and Fuki. It does not interact with five different nonchromosome 17 mutations that affect tail length. Thus, t-int is a tail modifier with surprisingly specific interactions.
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Du, Hong-Yan, Elena Pumbo, Akiko Shimamura, Adrianna Vlachos, Jeffrey M. Lipton, Fred Goldman, David B. Wilson, Philip Mason, and Monica Bessler. "Significance of Telomere Length Measurement in the Diagnosis of Dyskeratosis Congenita." Blood 110, no. 11 (November 16, 2007): 836. http://dx.doi.org/10.1182/blood.v110.11.836.836.
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Abstract Dyskeratosis congenita (DC) is a rare inherited bone marrow failure (BMF) syndrome. The classical features of DC include nail dystrophy, abnormal skin pigmentation, and mucosal leukoplakia. The diagnosis of DC can be difficult. Originally, the diagnosis was based on the presence of the classical mucocutaneous features. However, the identification of four genes responsible for DC (DKC1, TERC, TERT, and NOP10) showed that these mucocutaneous features are only present in a proportion of patients with DC. Additionally, screening for mutations in the affected genes is expensive and is negative in about 50% of patients with classical features of DC. The products of the genes mutated in DC are the components of the telomerase ribonucleoprotein complex, which is essential for telomere maintenance. Therefore it has been postulated that DC is a disease arising from excessive telomere shortening. Here we examined whether the measurement of telomeres could be used as a screening test to identify individuals with DC. For this purpose we examined telomere length in peripheral blood mononuclear cells from 169 patients who presented with bone marrow failure including 17 patients with DC, diagnosed by the presence of classical cutaneous features or the identification of mutations in DKC1, TERC or TERT, 28 patients with paroxysmal nocturnal hemoglobinuria, 25 patients with Diamond Blackfan anemia, 5 patients with Shwachman-Diamond syndrome, 8 patients with myelodysplastic syndrome, and 74 patients with aplastic anemia of unknown cause classified as idiopathic aplastic anemia. In addition we measured telomere length in 12 patients with idiopathic pulmonary fibrosis and in 45 individuals with a de novo deletion of chromosome 5p including the TERT gene. Their telomere lengths were compared with those of 202 age-matched healthy controls. Moreover, mutations were screened in the genes associated with DC. In cases where a mutation was identified, telomere length and mutations were also examined in all the family members. Our results show that all patients with DC and bone marrow failure have very short telomeres far below the first percentile of healthy controls. Not all mutation carriers, including some carriers of apparently dominant mutations, have very short telomeres. What is more, very short telomeres could be found in healthy individuals in these families, some of whom were not mutation carriers. These findings indicate that in patients with BMF the measurement of telomere length is a sensitive screening method for DC, whether very short telomeres in this setting are also specific for DC remains to be determined. However, in contrast to a previous study, we find that telomere length does not always identify mutation carriers in the families of DC.
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Avbelj, Magdalena, Husref Tahirovic, Marusa Debeljak, Maria Kusekova, Alma Toromanovic, Ciril Krzisnik, and Tadej Battelino. "High prevalence of thyroid peroxidase gene mutations in patients with thyroid dyshormonogenesis." European Journal of Endocrinology 156, no. 5 (May 2007): 511–19. http://dx.doi.org/10.1530/eje-07-0037.
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Objective: Thyroid dyshormonogenesis is a genetically heterogeneous group of inherited disorders in the enzymatic cascade of thyroid hormone synthesis that result in congenital hypothyroidism (CH). Thyroid peroxidase gene (TPO) mutations are one of the most common causes of thyroid dyshormonogenesis. The aim of this study was to identify TPO gene defects in a cohort of patients with thyroid dyshormonogenesis from Slovenia, Bosnia, and Slovakia. Design and methods: Forty-three patients with permanent CH and orthoptic thyroid glands from 39 unrelated families participated in the study. Mutational analysis of the TPO gene and part of its promoter consisted of single-stranded conformation polymorphism analysis, sequencing, and restriction fragment length polymorphism (RFLP) analysis. Results: TPO gene mutations were identified in 46% of participants. Seven different mutations were identified, four mutations of these being novel, namely 613C > T (R175X), 1519_1539del (A477_N483del), 2089G > A (G667S), and 2669G > A (G860R). Only a single allele mutation was identified in 65% of the TPO mutation carriers. Conclusions: The results showed a higher prevalence of TPO gene mutations in thyroid dyshormonogenesis when compared with published studies. The high percentage of single allele mutations implied possible intronic or regulatory TPO gene mutations or monoallelic expression.
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Ogihara, Y., and T. Ohsawa. "Molecular analysis of the complete set of length mutations found in the plastomes of TriticumAegilops species." Genome 45, no. 5 (October 1, 2002): 956–62. http://dx.doi.org/10.1139/g02-046.
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Precise location and nature of each of 14 length mutations detected among chloroplast DNAs of TriticumAegilops species by RFLP analysis were determined at the nucleotide sequence level. Each mutation was compared with at least three non-mutated wild-type plastomes as standards. These 14 length mutations were classified into 4 duplications and 10 deletions. One duplication occurred in the small single-copy region close to the border of the inverted repeat, and the remaining 13 length mutations took place in the large single-copy region. All length mutations occurred in the intergenic regions, suggesting that these length mutations do not affect plastid gene expression. Saltatory replication was the cause of all duplications, whereas intramolecular recombination mediated by short direct repeats played a substantial role in the deletions. Recurrent occurrences of certain deletion events were found in some AT-rich regions, which constituted hot spots for deletion. Out of four hypervariable regions detected among the grass plastomes, two (downstream of rbcL and a tRNA gene accumulated region) were still active after differentiation of Triticum and Aegilops complex.Key words: insertionsdeletions, plastome, TriticumAegilops, deletion hot spots, molecular mechanism.
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Tarlock, Katherine, Todd M. Cooper, Todd A. Alonzo, Robert Gerbing, Jessica Pollard, Richard Aplenc, E. Anders Kolb, Alan S. Gamis, and Soheil Meshinchi. "Mutational Concordance from Diagnosis and Relapse in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group." Blood 128, no. 22 (December 2, 2016): 2846. http://dx.doi.org/10.1182/blood.v128.22.2846.2846.
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Abstract The range of genomic drivers of leukemogenesis and clonal nature of the disease illustrate the heterogeneity of the mutational spectrum in AML. Genomic interrogation of the evolution of AML has begun to highlight the scope of somatic changes that occur between diagnosis and relapse. A total of 1,214 patients were treated on the Children's Oncology Group trials AAML03P1 and AAML0531, of which 398 had relapse after initial remission. Of this cohort, 201 patients had matching diagnostic and relapse specimens for molecular profiling for the most common somatic mutations in pediatric AML (FLT3/ITD, FLT3/ALM, NPM1, CEBPA, WT1, NRAS, and KIT). Sequencing techniques included PCR with Sanger sequencing for detection of point mutations and indels and fragment length analysis for FLT3/ITD. In the cohort, FLT3/ITD was detected in 31/201 (15%) cases at diagnosis. Of the cases with diagnostic ITD, 22 (71%) relapsed with FLT3/ITD. Conversely, of the 28 cases with FLT3/ITD detected at relapse, 6 (21%) did not have detectable ITD at diagnosis. Overall, there were 37 patients (18%) with FLT3/ITD mutations detected at either time point. Of the 37 patients, 22 (59%) demonstrated stability of the mutation from diagnosis to relapse. Discordant mutation status was observed in 15 patients (41%). Among the discordant patients, 9 had FLT3/ITD detected at diagnosis only. Conversely, 6 patients were ITD-positive at relapse only, demonstrating disease evolution with continued mutational acquisition (Table 1). In every discordant case, ultra sensitive PCR analysis confirmed absence of an ITD. The median ITD allelic ratio (AR) for patients with concordant status was 0.47 (range 0.03-2.67) vs. 0.24 (range 0.04-0.47) for those with disappearance of the ITD at relapse, suggesting an association of diagnostic AR with mutation stability. NPM1 mutations were detected in 8 patients at diagnosis and 100% concordance was observed in the cohort. CEBPA mutations were detected in 6 patients at diagnosis, and in 5 cases remained at relapse. One patient had a CEBPA mutation detected at diagnosis only. FLT3/ALM mutations were detected in 7 patients at either time point. Seven patients had an ALM at diagnosis, however concordance was observed in 2 cases, whereas 4 patients had detection at diagnosis only. There were 22 patients (11%) with NRAS mutations detected at either time point. Diagnostic NRAS mutations were detected in 18 patients, while only 3 (17%) had the identical mutation detected at relapse, as one patient had a distinct mutational sequence present at relapse. NRAS mutations were detected at diagnosis only in 13 patients (59%), where as 5 patients (23%) had a mutation detected at relapse only. NRAS was the most discordant mutations analyzed, with only 3/22 patients (14%) demonstrating stability of the mutation from diagnosis to relapse (Table 1). WT1 exon 17 indels were observed in 24 patients (12%) at either time point. Nineteen patients had diagnostic mutations, with 18 patients demonstrating stability at relapse. Five patients had mutations detected at relapse only. Overall, concordance was observed in 18 patients (75%). Only 1 alteration was detected at diagnosis in all patients, however 6 patients with concordant WT1 status had multiple indels detected at relapse, demonstrating continued mutational acquisition. KIT mutations (missense and indels) in exons 8 (n=11) and 17 (n=7) were detected in 17 patients. Mutational concordance was observed in 7 patients. Eight patients had mutations detected at diagnosis only, while 2 patients had mutations detected at relapse only (Table 1). We demonstrate the complexity of the evolving somatic landscape from diagnosis to relapse in pediatric AML. The stability of NPM1 mutations, considered an early leukemogenic event, is in contrast to the discordant NRAS and KIT mutations. There was evolution of FLT3/ITD status, and we observed overall higher ARs in the concordant cohort, perhaps suggesting mutations in this cohort served as stronger leukemic drivers. Further investigation on the biologic implications and clonal prevalence is critical to determine a mutation's significance in leukemogenesis, timing of acquisition, and if appropriate for therapeutic targeting and disease monitoring. Table 1 Mutational concordance from diagnosis to relapse. Legend: Discordant D+/R-: Discordant status with diagnostic only positive Discordant D-/R+: Discordant status with relapse only positive Table 1. Mutational concordance from diagnosis to relapse. / Legend:. / Discordant D+/R-: Discordant status with diagnostic only positive. / Discordant D-/R+: Discordant status with relapse only positive Disclosures No relevant conflicts of interest to declare.
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Lieb, M., E. Allen, and D. Read. "VERY SHORT PATCH MISMATCH REPAIR IN PHAGE LAMBDA: REPAIR SITES AND LENGTH OF REPAIR TRACTS." Genetics 114, no. 4 (December 1, 1986): 1041–60. http://dx.doi.org/10.1093/genetics/114.4.1041.
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ABSTRACT Five amber mutations in the repressor (cl) gene of bacteriophage λ recombine anomalously with nearby cl mutations. When any of these markers is used in four-factor crosses, cl + recombinants that are expected to require three crossovers occur at high frequencies. These recombinants are attributable to very-short-patch (VSP) repair of specific mismatches in DNA heteroduplexes formed during recombination between the markers flanking cl. The sites of the repairprone mutations and the lengths of repair tracts have now been determined. Amber mutations subject to VSP repair are C to T transitions in (see PDF), the sequence methylated by the product of gene dcm, and also in the related 5′CAGG or 5′CCAG sequences. Ambers arising in CAG sequences found in other contexts, or in codons other than CAG, were not subject to VSP repair. Repair tracts rarely, if ever, exceed ten nucleotides in length, and can be as short as two nucleotides. A repair-prone mutation does not stimulate recombination between flanking cl markers.
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Aalbers, Anna M., Rodrigo T. Calado, Neal S. Young, Christian M. Zwaan, Colin O. Wu, Sachiko Kajigaya, Eva A. Coenen, et al. "Telomere Length and Telomerase Complex Mutations in Pediatric Acute Myeloid Leukemia." Blood 120, no. 21 (November 16, 2012): 1482. http://dx.doi.org/10.1182/blood.v120.21.1482.1482.
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Abstract Abstract 1482 Inherited loss-of-function mutations in the telomerase complex gene TERT have recently been implicated as risk factors for acute myeloid leukemia (AML) in adults. The telomerase complex is expressed in highly proliferative cells, and is responsible for maintaining telomeres, which cap the ends of chromosomes and protect genomic DNA from eroding during cell division. Impaired telomerase function can result in extremely short telomeres, which limits the proliferative capacity of progenitor cells, and can also lead to chromosomal instability, thus predisposing to malignant transformation. In pediatric AML, the frequency of such mutations, and the association of telomere length with cytogenetic, molecular, and clinical characteristics and outcome, are unknown. In a cohort of 168 pediatric AML patients, we determined the frequency of telomerase complex gene mutations and leukemic cell telomere length, and correlated this with prognostic cytogenetic characteristics (inv(16), t(8;21), MLL rearrangements, normal karyotype, other aberrations), molecular aberrations (CEBPA double mutations, NPM1 mutations, FLT3/ITD, WT1 mutations), clinical characteristics, and outcome. No mutations were present in TERC. Three heterozygous variants in TERT, E327D, T726M, and A1062T, were identified in eight of 168 pediatric AML patients (carrier frequency 0.048). In three of six patients carrying A1062T, remission material was available, in which germ-line origin of the variant was confirmed. The variants E327D and T726M were absent, but A1062T was present in a cohort of 406 geographically matched controls (carrier frequency 0.049). Telomerase activity, as determined by TRAP assay in reconstitution experiments, of the novel E327D variant was unaffected, as was the previously published activity of T726M; the earlier reported activity of A1062T was reduced to 60%. Telomere length of leukemic cells was not associated with age, sex, prognostic cytogenetic subgroup, complex karyotype, or expression levels of telomerase and shelterin complex genes. However, patients carrying the high-risk molecular aberration FLT3/ITD had significantly shorter telomeres than did patients with favorable NPM1 mutation or CEBPA double mutations. Telomere length was not associated with overall survival, event-free survival, or cumulative incidence of relapse. We conclude that, in pediatric AML, telomerase complex mutations do not confer a risk for leukemia development, and although short telomeres correlate with the high-risk molecular aberration FLT3/ITD, telomere length of leukemic cells obtained at diagnosis does not correlate with adverse outcome in this pediatric AML cohort. Disclosures: No relevant conflicts of interest to declare.
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Ben David, Y., A. Chetrit, G. Hirsh-Yechezkel, E. Friedman, B. D. Beck, U. Beller, G. Ben-Baruch, et al. "Effect of BRCA Mutations on the Length of Survival in Epithelial Ovarian Tumors." Journal of Clinical Oncology 20, no. 2 (January 15, 2002): 463–66. http://dx.doi.org/10.1200/jco.2002.20.2.463.
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PURPOSE: To study the role of BRCA mutations in ovarian cancer survival. PATIENTS AND METHODS: Blood samples and specimens of ovarian tumors (whenever blood samples were not available) at the time of the primary surgery were obtained in the course of a nationwide case-control study of women with ovarian cancer in Israel. The three common BRCA mutations in Israel (185delAG, 5382insC, and 6174delT) were analyzed with a multiplex polymerase chain reaction to amplify the exons containing the three mutations using fluor-labeled primers in a single reaction. Because each mutation is a small insertion or deletion, they can be detected as length polymorphisms. Patients were followed for up to 5 years (range, 20 to 64 months). Statistical analysis was performed using the Kaplan-Meier method and the log-rank test. Stepwise Cox regression analysis was used for determination of independent prognostic factors. RESULTS: This report is based on 896 blood or tumor specimens analyzed for the presence of the BRCA mutations. Of these, 234 women (26.1%) were found to be positive. A significant difference in survival pattern was found between BRCA1/BRCA2 carriers and noncarriers among the women with invasive ovarian cancer (median survival, 53.4 months v 37.8 months; 3-year survival, 65.8% v 51.9%, respectively). These differences were independent of age at diagnosis or stage of the disease. CONCLUSION: Our data indicate that the survival of patients with ovarian cancer is affected by BRCA germline mutation, at least in the early years after diagnosis.
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Romppanen, Eeva-Liisa, and Ilkka Mononen. "Detection of the Finnish-Type Congenital Nephrotic Syndrome by Restriction Fragment Length Polymorphism and Dual-Color Oligonucleotide Ligation Assays." Clinical Chemistry 46, no. 6 (June 1, 2000): 811–16. http://dx.doi.org/10.1093/clinchem/46.6.811.
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Abstract Background: Congenital nephrotic syndrome of Finnish type (NPHS1) is an autosomal recessive disorder characterized by severe proteinuria of intrauterine onset. Ninety-four percent of the Finnish NPHS1 chromosomes have been reported to carry either a 2-bp deletion in exon 2 (FinMajor) or a nonsense mutation in exon 26 (FinMinor) of the NPHS1 gene. The high prevalence of only two mutations in the Finnish population enables the use of molecular techniques in the diagnosis of NPHS1 and for carrier screening. Methods and Results: We describe two different molecular methods for the detection of the NPHS1 mutations: a PCR-restriction fragment length polymorphism (PCR-RFLP) and a dual-color oligonucleotide ligation assay (OLA). The dual-color OLA, which enables simultaneous detection of the NPHS1 FinMajor and FinMinor mutations, can be used for rapid analysis of large sets of samples. The analysis of 2004 Finnish blood samples revealed 34 carriers of the FinMajor mutation and 1 carrier of the FinMinor mutation, indicating a carrier frequency of 1:59 (95% confidence interval, 1:89–1:44) for the NPHS1 FinMajor mutation and 1:2004 (95% confidence interval, 0 to 1:677) for the NPHS1 FinMinor mutation, respectively. Conclusion: PCR-RFLP and dual-color OLA are suitable for molecular diagnosis and carrier screening of the major mutations that cause NPHS1.
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Alder, Jonathan K., Vidya Sagar Hanumanthu, Margaret A. Strong, Amy E. DeZern, Susan E. Stanley, Clifford M. Takemoto, Ludmila Danilova, et al. "Diagnostic utility of telomere length testing in a hospital-based setting." Proceedings of the National Academy of Sciences 115, no. 10 (February 20, 2018): E2358—E2365. http://dx.doi.org/10.1073/pnas.1720427115.
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Telomere length (TL) predicts the onset of cellular senescence in vitro but the diagnostic utility of TL measurement in clinical settings is not fully known. We tested the value of TL measurement by flow cytometry and FISH (flowFISH) in patients with mutations in telomerase and telomere maintenance genes. TL had a discrete and reproducible normal range with definable upper and lower boundaries. While TL above the 50th age-adjusted percentile had a 100% negative predictive value for clinically relevant mutations, the lower threshold in mutation carriers was age-dependent, and adult mutation carriers often overlapped with the lowest decile of controls. The extent of telomere shortening correlated with the age at diagnosis as well as the short telomere syndrome phenotype. Extremely short TL caused bone marrow failure and immunodeficiency in children and young adults, while milder defects manifested as pulmonary fibrosis-emphysema in adults. We prospectively examined whether TL altered treatment decisions for newly diagnosed idiopathic bone marrow failure patients and found abnormally short TL enriched for patients with mutations in some inherited bone marrow failure genes, such as RUNX1, in addition to telomerase and telomere maintenance genes. The result was actionable, altering the choice of treatment regimen and/or hematopoietic stem cell donor in one-fourth of the cases (9 of 38, 24%). We conclude that TL measurement by flowFISH, when used for targeted clinical indications and in limited settings, can influence treatment decisions in ways that improve outcome.
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Adams, A. K., and C. Holm. "Specific DNA replication mutations affect telomere length in Saccharomyces cerevisiae." Molecular and Cellular Biology 16, no. 9 (September 1996): 4614–20. http://dx.doi.org/10.1128/mcb.16.9.4614.
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To investigate the relationship between the DNA replication apparatus and the control of telomere length, we examined the effects of several DNA replication mutations on telomere length in Saccharomyces cerevisiae. We report that a mutation in the structural gene for the large subunit of DNA replication factor C (cdc44/rfc1) causes striking increases in telomere length. A similar effect is seen with mutations in only one other DNA replication gene: the structural gene for DNA polymerase alpha (cdc17/pol1) (M.J. Carson and L. Hartwell, Cell 42:249-257, 1985). For both genes, the telomere elongation phenotype is allele specific and appears to correlate with the penetrance of the mutations. Furthermore, fluorescence-activated cell sorter analysis reveals that those alleles that cause elongation also exhibit a slowing of DNA replication. To determine whether elongation is mediated by telomerase or by slippage of the DNA polymerase, we created cdc17-1 mutants carrying deletions of the gene encoding the RNA component of telomerase (TLC1). cdc17-1 strains that would normally undergo telomere elongation failed to do so in the absence of telomerase activity. This result implies that telomere elongation in cdc17-1 mutants is mediated by the action of telomerase. Since DNA replication involves transfer of the nascent strand from polymerase alpha to replication factor C (T. Tsurimoto and B. Stillman, J. Biol. Chem. 266:1950-1960, 1991; T. Tsurimoto and B. Stillman, J. Biol. Chem. 266:1961-1968, 1991; S. Waga and B. Stillman, Nature [London] 369:207-212, 1994), one possibility is that this step affects the regulation of telomere length.
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Hosen, Ismail, P. Sivaramakrishna Rachakonda, Barbara Heidenreich, Petra J. de Verdier, Charlotta Ryk, Gunnar Steineck, Kari Hemminki, and Rajiv Kumar. "Mutations inTERTpromoter andFGFR3and telomere length in bladder cancer." International Journal of Cancer 137, no. 7 (April 7, 2015): 1621–29. http://dx.doi.org/10.1002/ijc.29526.
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Jang, Jeong-Won, Jin-Seoub Kim, Hye-Seon Kim, Kwon-Yong Tak, Soon-Kyu Lee, Hee-Chul Nam, Pil-Soo Sung, et al. "Significance of TERT Genetic Alterations and Telomere Length in Hepatocellular Carcinoma." Cancers 13, no. 9 (April 30, 2021): 2160. http://dx.doi.org/10.3390/cancers13092160.
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Telomerase reverse transcriptase (TERT) mutations are reportedly the most frequent somatic genetic alterations in hepatocellular carcinoma (HCC). An integrative analysis of TERT-telomere signaling during hepatocarcinogenesis is lacking. This study aimed to investigate the clinicopathological association and prognostic value of TERT gene alterations and telomere length in HCC patients undergoing hepatectomy as well as transarterial chemotherapy (TACE). TERT promoter mutation, expression, and telomere length were analyzed by Sanger sequencing and real-time PCR in 305 tissue samples. Protein–protein interaction (PPI) analysis was performed to identify a set of genes that physically interact with TERT. The PPI analysis identified eight key TERT-interacting genes, namely CCT5, TUBA1B, mTOR, RPS6KB1, AKT1, WHAZ, YWHAQ, and TERT. Among these, TERT was the most strongly differentially expressed gene. TERT promoter mutations were more frequent, TERT expression was significantly higher, and telomere length was longer in tumors versus non-tumors. TERT promoter mutations were most frequent in HCV-related HCCs and less frequent in HBV-related HCCs. TERT promoter mutations were associated with higher TERT levels and longer telomere length and were an independent predictor of worse overall survival after hepatectomy. TERT expression was positively correlated with tumor differentiation and stage progression, and independently predicted shorter time to progression after TACE. The TERT-telomere network may have a crucial role in the development and progression of HCC. TERT-telomere abnormalities might serve as useful biomarkers for HCC, but the prognostic values may differ with tumor characteristics and treatment.
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Han, Bing, Bo Liu, and Yongqiang Zhao. "Telomerase Gene Mutation Screening and Telomere Length Detection in Chinese Patients with Bone Marrow Failure Syndrome." Blood 112, no. 11 (November 16, 2008): 1047. http://dx.doi.org/10.1182/blood.v112.11.1047.1047.
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Abstract Background Acquired bone marrow failure syndrome (BMF) is a group of diseases include aplastic anemia(AA), melodysplastic syndrome (MDS) and paraoxymal nocturnal hemoglobinuria (PNH). Some BMF patients have short telomeres in their peripheral nucleated cells. The length of telomere is maintained by a group of enzymes called telomerase complex. The core components of this complex are a RNA template and a reverse transcriptase, called TERC and TERT, respectively. Recently several studies in the west and Japan have disclosed the presence of telomerase complex gene mutation in a small group of patients with acquired bone marrow failure. They speculated that this small group of patients might represent a subset of cryptogenic Dyskeratosis Congenita (DKC), in which the premature exhaustion of hematopoietic reservoir is caused by mutations in the telomerase gene. This group of patients, though very small in number, would benefit from early bone marrow transplantation instead of traditional immunosuppressive therapy. The incidence of aplastic anemia in Chinese people is relatively high compared with that in the western country. But there has so far been no study in China about the incidence of telomerase gene mutation in acquired bone marrow failure and its relationship with telomere length. Objectives To study the incidence of telomerase gene (namely TERC and TERT ) mutation in Chinese patients with acquired bone marrow failure and explore its relationship with telomere shortening. Methods Blood samples from 90 patients with AA, MDS, and PNH in northern China were collected and performed TERC and TERT mutation analysis. Telomere length was measured by Southern blotting and compared with their normal counterparts. Results 2 TERC mutations (n37 A→G, reported previously ; n66G→C) and 2 TERT mutations (n1870G→T (E/*); n1780G→T (S/I) ) were identified in 90 BMF patients. Among them, 3 mutations are reported first time. 1 patient with TERT mutation, however, was finally diagnosed as DKC instead of acquired AA, making the incidence of telomerase gene mutation in Chinese people with acquired bone marrow failure 3.4%, similar to that of the western people. Southern Blot analysis showed the small group of patients carrying TERC and TERT mutations has very short telomeres, compared with normal controls and with their aplastic counterparts. Conclusions The incidence of telomerase gene mutation in Chinese people with acquired bone marrow failure is 3.4%, similar to that of the western people. This small group of patients has very short telomeres, it is thus clinically important to screen for this small group of patients.
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Watts, Justin M., Bogdan Dumitriu, Patrick Hilden, Christina Chen, Franck Rapaport, Ashwin Kishtagari, Jihae Ahn, et al. "Telomere Length Is Associated with Specific Mutations and Mutation Classes in Patients with Acute Myeloid Leukemia." Blood 124, no. 21 (December 6, 2014): 2280. http://dx.doi.org/10.1182/blood.v124.21.2280.2280.
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Abstract It is unknown if telomere length (TL) is associated with clinical outcome or molecular profile in acute myeloid leukemia (AML). We collected tumor samples from 67 AML patients treated at Memorial Sloan Kettering Cancer Center. DNA extraction was performed using viably frozen peripheral blood and bone marrow mononuclear cells. RainDance was used to amplify all exons of a set of 30 genes commonly mutated in AML. Capture was followed by next-generation sequencing; mutations were called if the variant was supported by >5% of the total number of reads (minimum >10 reads). TL was measured as mean telomere content by qPCR. Patients were assessed for FLT3 and NPM1 mutations, cytogenetics, and outcomes by chart review. Results In our 67 patient AML cohort, median TL was 5.22 kb (range 3.73-8.76). Median age was 64.1 years (range 26.2-84.4). While in healthy individuals TL shortens with age, in our cohort there was no association (R2=0.043). There was no difference in TL between newly diagnosed (ND) and relapsed/refractory (RR) patients or between de novo and secondary AML patients. In the 45 ND patients, there was a trend of early improved survival following sample collection in the longest TL tertile compared to the middle and shortest TL tertiles (86.7% vs. 60.0% and 33.3% at 6 months); however, this association was not statistically significant (p=0.662) (Fig 1). In the 22 RR patients, there was also a trend toward improved OS in the longest TL tertile (60.0% vs. 11.1% and 25.0%, p=0.284). In ND patients, there was no association between TL and primary induction failure or relapse-free survival. Targeted sequencing data for 30 myeloid genes were available in 62 of the 67 patients. Analysis of single mutation correlation with TL showed that patients with IDH1 mutations had significantly longer TL than those without (p=0.02) (Table 1). Moreover, mutations in a set of genes associated with epigenetic functions (IDH1/2, ASXL1, DNMT3A, and TET2) also correlated with longer TL when examined together as a group (p=0.073).FLT3-ITD mutations were associated with shorter TL (p=0.084). The median ages of patients with IDH1 or FLT3 mutations were not different from the rest of the cohort. Of note, FLT3-mutated patients did have a higher WBC than FLT3 wild-type patients (p<0.001), suggesting that increased proliferative rate may be associated with shorter TL. Patients with RUNX1 mutations, t(8;21), or inv(16) also had a non-significant trend toward shorter TL (Table 1), and when we examined FLT3, RUNX1, t(8;21), and inv(16) together as a group, there was an association with shorter TL (p=0.026). There was no association between TL and NPM1 mutations. There was no difference in TL in patients with normal (n=35) vs. abnormal karyotype (n=31). Conclusion There was a trend of early improved survival for patients with the longest TL, suggesting that longer TL may be associated with better response rates to chemotherapy. However, the analysis was limited by the relatively small size of our cohort, andlarger studies are needed to further assess this association. We also demonstrated that IDH1 mutations are associated with longer TL (p=0.02), and that TL in general may be associated with specific classes of AML mutations. For example, mutations in transcription factors or receptor tyrosine kinases conferring a proliferative advantage may be associated with shorter TL, while mutations in epigenetic modifiers appear to be associated with longer TL. This is a novel and intriguing finding that warrants further study of TL, mutational profile, and epigenetic alterations in AML. Table 1 Mutation N Median TL (range) p-value IDH1 0.020 negative 56 5.09 (3.73,8.76) positive 6 6.32 (4.81,7.72) IDH2 0.870 negative 59 5.16 (3.73,8.76) positive 3 5.63 (4.10,6.54) DNMT3A 0.697 negative 53 5.08 (3.73,8.76) positive 9 5.53 (4.53,6.29) TET2 0.423 negative 55 5.16 (3.73,7.85) positive 7 5.53 (4.40,8.76) ASXL1 0.219 negative 59 5.10 (3.73,7.85) positive 3 5.56 (5.52,8.76) FLT3-ITD 0.084 negative 46 5.54 (3.95,8.76) positive 12 4.72 (3.97,8.00) RUNX1 0.856 negative 57 5.22 (3.73,8.76) positive 5 4.89 (4.10,6.34) t(8;21) 0.588 negative 64 5.24 (3.73,8.76) positive 2 4.87 (4.81,4.93) inv(16) 0.302 negative 63 5.22 (3.73,8.76) positive 3 4.72 (4.20,5.26) Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Shen, Erica, Joanne Xiu, Giselle Y. Lopez, Rex Bentley, Ali Jalali, Amy B. Heimberger, Matthew N. Bainbridge, Melissa L. Bondy, and Kyle M. Walsh. "POT1 mutation spectrum in tumour types commonly diagnosed among POT1-associated hereditary cancer syndrome families." Journal of Medical Genetics 57, no. 10 (January 14, 2020): 664–70. http://dx.doi.org/10.1136/jmedgenet-2019-106657.
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BackgroundThe shelterin complex is composed of six proteins that protect and regulate telomere length, including protection of telomeres 1 (POT1). Germline POT1 mutations are associated with an autosomal dominant familial cancer syndrome presenting with diverse malignancies, including glioma, angiosarcoma, colorectal cancer and melanoma. Although somatic POT1 mutations promote telomere elongation and genome instability in chronic lymphocytic leukaemia, the contribution of POT1 mutations to development of other sporadic cancers is largely unexplored.MethodsWe performed logistic regression, adjusted for tumour mutational burden, to identify associations between POT1 mutation frequency and tumour type in 62 368 tumours undergoing next-generation sequencing.ResultsA total of 1834 tumours harboured a non-benign mutation of POT1 (2.94%), of which 128 harboured a mutation previously reported to confer familial cancer risk in the setting of germline POT1 deficiency. Angiosarcoma was 11 times more likely than other tumours to harbour a POT1 mutation (p=1.4×10−20), and 65% of POT1-mutated angiosarcoma had >1 mutations in POT1. Malignant gliomas were 1.7 times less likely to harbour a POT1 mutation (p=1.2×10−3) than other tumour types. Colorectal cancer was 1.2 times less likely to harbour a POT1 mutation (p=0.012), while melanoma showed no differences in POT1 mutation frequency versus other tumours (p=0.67).ConclusionsThese results confirm a role for shelterin dysfunction in angiosarcoma development but suggest that gliomas arising in the context of germline POT1 deficiency activate a telomere-lengthening mechanism that is uncommon in gliomagenesis.
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Arnold, Dirk V., and Hans-Georg Beyer. "On the Behaviour of Evolution Strategies Optimising Cigar Functions." Evolutionary Computation 18, no. 4 (December 2010): 661–82. http://dx.doi.org/10.1162/evco_a_00023.
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This paper studies the performance of multi-recombinative evolution strategies using isotropically distributed mutations with cumulative step length adaptation when applied to optimising cigar functions. Cigar functions are convex-quadratic objective functions that are characterised by the presence of only two distinct eigenvalues of their Hessian, the smaller one of which occurs with multiplicity one. A simplified model of the strategy's behaviour is developed. Using it, expressions that approximately describe the stationary state that is attained when the mutation strength is adapted are derived. The performance achieved by cumulative step length adaptation is compared with that obtained when using optimally adapted step lengths.
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Ran, Yanchao, Aiping Zheng, and Patrick H. Thibodeau. "Structural analysis reveals pathomechanisms associated with pseudoxanthoma elasticum–causing mutations in the ABCC6 transporter." Journal of Biological Chemistry 293, no. 41 (August 28, 2018): 15855–66. http://dx.doi.org/10.1074/jbc.ra118.004806.
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Mutations in ABC subfamily C member 6 (ABCC6) transporter are associated with pseudoxanthoma elasticum (PXE), a disease resulting in ectopic mineralization and affecting multiple tissues. A growing number of mutations have been identified in individuals with PXE. For most of these variants, no mechanistic information is available regarding their role in normal and pathophysiologies. To assess how PXE-associated mutations alter ABCC6 biosynthesis and structure, we biophysically and biochemically evaluated the N-terminal nucleotide-binding domain. A high-resolution X-ray structure of nucleotide-binding domain 1 (NBD1) of human ABCC6 was obtained at 2.3 Å that provided a template on which to evaluate PXE-causing mutations. Biochemical analysis of mutations in this domain indicated that multiple PXE-causing mutations altered its structural properties. Analyses of the full-length protein revealed a strong correlation between the alterations in NBD properties and the processing and expression of ABCC6. These results suggest that a significant fraction of PXE-associated mutations located in NBD1 causes changes in its structural properties and that these mutation-induced alterations directly affect the maturation of the full-length ABCC6 protein.
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Feng, Ru, Lixia Hao, Yongmin Zhang, Yongqiang Wei, Fen Huang, and Changxin Yin. "Analysis of the JAK2 Gene cDNA Full-Length In One Chinese Familial Myeloproliferative Disorders." Blood 116, no. 21 (November 19, 2010): 5056. http://dx.doi.org/10.1182/blood.v116.21.5056.5056.
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Abstract Abstract 5056 Introduction: JAK2V617F point mutation have been confirmed to be one of the major molecular mechanism of BCR/ABL negative myeloproliferative disorders(MPD). Besides, some other gene mutations such as JAK2 exon12, MPL W515L/K, c-mpl and EPOR have extended the scope of the research in this field. Most of the MPD patients are sporadic and there are seldom reports in Chinese familial MPD. 2008 ASH metting we have reported in a Chinese family of MPD's findings, the two brothers in our hospital diagnosis for MPD (one is a PV, another is ET), then we investigated the 15 members of the family. We discovered that there were three male members carried the JAK2V617F mutation in this family, including the two MPD patients and their father, which affected in two generations. All the family members were confirmed as BCR/ABL, MPL W515L/K, c-mpl, and EPOR negative. Subsequently, in order to understand the existence of family members in addition to the gene JAK2 V617F mutation, the existence of JAK2 gene mutations in other parts of the? if other mutations in existence and the high incidence of family members of MPD? We focus on the cDNA full-length of JAK2 gene to provide some theory basis on the pathogenesis in MPD. Methods: A total of 15 family members were enrolled in our study, including 2 brothers of MPD patients (the older one was thrombocythemia (ET), and another is polycythemia vera (PV)) and the other members in the same family. The mRNA of mononuclear cells from peripheral blood sample was extracted according to the manufacturer's instruction (TAKARA). RT-PCR and DNA sequencing have been used to analyze the cDNA full-length of the JAK2 gene. Results: All of the samples can be analyzed for JAK2 cDNA full-length. 3 members carried the JAK2V617F mutation (1849G®T) in this family, including the two MPD patients and their father. And the older brother was homozygous mutation and the other two were heterozygous mutation. All of the 15 samples were JAK2 exon12 gene mutation negative. 2 persons who were the male ET patient's children had a heterozygous mutation (380G®A) in JAK2 exon 3, caused a glycine-to-asparticacid substitution at position 127. Besides, 13 persons had 489C®T mutation in exon 4 and 14 persons had 2490G→A mutation in exon 17 in this family, But they were both same-sense mutation. Conclusion: It is necessary to do routine analysis of blood and other related inspection for MPD patient's family members, so as to make diagnosis earlier. However, we are not sure that the sequencing results are unique to all the familial MPD and need to be confirmed by more cases. We still do not determine the current discovery point mutations have biological significance, still need to be further explored. Disclosures: No relevant conflicts of interest to declare.
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Muntaj, Shaik, K. Devaraju, M. Kamate, A. Vedamurthy, and Kruthika-Vinod TP. "Genetic Screening of Selected Disease-Causing Mutations in Glutaryl-CoA Dehydrogenase Gene among Indian Patients with Glutaric Aciduria Type I." Journal of Pediatric Genetics 06, no. 03 (March 7, 2017): 142–48. http://dx.doi.org/10.1055/s-0037-1599202.
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AbstractGlutaric aciduria type I (GA-I) is an organic aciduria caused by glutaryl-CoA dehydrogenase (GCDH) deficiency. There are limited studies on GA-I from India. A total of 48 Indian GA-I patients were screened for selected disease-causing mutations such as R402W, A421V, A293T, R227P, and V400M using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Among these patients, 9 (18.8%) had R402W mutation, and none had A421V, A293T, R227P, or V400M mutation. One low excretor mutation (P286S) and several novel mutations (I152M, Q144P, and E414X) were also found in this study. We conclude that among selected mutations, R402W is the most common mutation found among Indian GA-I patients.
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Borie, Raphael, Diane Bouvry, Vincent Cottin, Clement Gauvain, Aurélie Cazes, Marie-Pierre Debray, Jacques Cadranel, et al. "Regulator of telomere length 1 (RTEL1) mutations are associated with heterogeneous pulmonary and extra-pulmonary phenotypes." European Respiratory Journal 53, no. 2 (February 2019): 1800508. http://dx.doi.org/10.1183/13993003.00508-2018.
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Regulator of telomere length 1 (RTEL1) mutations have been evidenced in 5–9% of familial pulmonary fibrosis; however, the phenotype of patients with interstitial lung disease (ILD) and RTEL1 mutations is poorly understood.Whole exome sequencing was performed in 252 probands with ILD and we included all patients with ILD and RTEL1 mutation. RTEL1 expression was evaluated by immunochemistry in the lungs of controls, as well as in RTEL1 and telomerase reverse transcriptase (TERT) mutation carriers.We identified 35 subjects from 17 families. Median age at diagnosis of ILD was 53.1 years (range 28.0–80.6). The most frequent pulmonary diagnoses were idiopathic pulmonary fibrosis (n=20, 57%), secondary ILD (n=7, 20%) and unclassifiable fibrosis or interstitial pneumonia with autoimmune features (n=7, 20%). The median transplant-free and overall survival periods were 39.2 months and 45.3 months, respectively. Forced vital capacity at diagnosis was the only factor associated with decreased transplant-free survival. Extra-pulmonary manifestations were less frequent as compared to other telomere-related gene mutation carriers. A systematic analysis of the literature identified 110 patients with ILD and RTEL1 mutations (including this series) and confirmed the heterogeneity of the pulmonary phenotype, the prevalence of non-idiopathic diseases and the low prevalence of extra-pulmonary manifestations.Immunohistochemistry showed that RTEL1 was expressed by bronchial and alveolar epithelial cells, as well as by alveolar macrophages and lymphocytes, but not by fibroblasts.
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Kalakonda, Nagesh, Dominic G. Rothwell, J. Howard Scarffe, and John D. Norton. "Detection of N-Ras codon 61 mutations in subpopulations of tumor cells in multiple myeloma at presentation." Blood 98, no. 5 (September 1, 2001): 1555–60. http://dx.doi.org/10.1182/blood.v98.5.1555.
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Activating point mutations in codons 12, 13, or 61 of the K-ras and N-ras genes have been reported to occur in up to 40% of patients with multiple myeloma at presentation. In a study of 34 presentation myeloma cases using a sensitive polymerase chain reaction-restriction fragment length polymorphism strategy on enriched tumor cell populations, the present study detected N-ras codon 61 mutation-positive cells in all patients. Quantitative plaque hybridization using allele-specific oligonucleotide probes showed that in the majority of patients, ras mutation-positive cells comprise only a subpopulation of the total malignant plasma cell compartment (range, 12%-100%). Using clonospecific point mutations in the 5′ untranslated region of the BCL6 gene to quantitate clonal B cells in FACS-sorted bone marrow populations from 2 patients, the representation of ras mutation-positive cells was independent of immunophenotype. These observations imply that mutational activation of N-ras codon 61 is a mandatory event in the pathogenesis of multiple myeloma; such mutations provide a marker of intraclonal heterogeneity that may originate at an earlier ontologic stage than immunophenotypic diversification of the malignant B cell clone.
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Lennerz, Jochen K., Birgit Schif, Christian W. Kohler, Stefan Bentink, Markus Kreuz, Ingo Melzner, Lorenz Trümper, Markus Löffler, Rainer Spang, and Peter Moeller. "SOCS1 Mutation Subtypes Predict Divergent Outcomes in DLBCL Patients." Blood 120, no. 21 (November 16, 2012): 419. http://dx.doi.org/10.1182/blood.v120.21.419.419.
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Abstract Abstract 419 Suppressor of cytokine signaling 1 (SOCS1) is frequently mutated in Hodgkin, primary mediastinal and diffuse large B-cell lymphomas (DLBCL). In the primary mediastinal B-cell lymphoma line MedB-1, mutated SOCS1 abnormally stabilizes phospho-JAK2, thereby enhances STAT signaling leading to continuous proliferation. Here, we evaluated the prognostic value of SOCS1 mutations by full-length gene sequencing of SOCS1 in 154 comprehensively characterized DLBCL cases. By sequence analysis, we identified 90 SOCS1 mutations in 16% of lymphomas. We defined two distinct subtypes with respect to putative mutational consequences: those predicting the full-length (minor) and a truncated protein (major), respectively. Neither the SOCS1 mutation group, nor minor/major subgroups can be distinguished by clinical phenotype; however, assignment of four established expression-based classifiers revealed significant associations of SOCS1 major cases with germinal center- and specific pathway activation pattern signatures. Above all, SOCS1 major cases had an excellent overall survival, even better than the GCB-like subgroup (see Figure). SOCS1 minor cases had a dismal survival, even worse than the ABC gene signature group (see Figure). SOCS1 mutation subsets retain prognostic significance in uni- and multivariate analyses. Thus, if a SOCS1 mutation is present, the mutation type is an important single gene prognostic biomarker in DLBCL. Disclosures: No relevant conflicts of interest to declare.
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Kuo, Ming-Chung, Tung-Huei Lin, Chien-Feng Sun, Tung-Liang Lin, Jin-Hou Wu, Po-Nan Wang, Ying-Jung Huang, Hung Chang, Ting-Yu Huang, and Lee-Yung Shih. "The clinical and prognostic relevance of driver mutations in 203 Taiwanese patients with primary myelofibrosis." Journal of Clinical Pathology 71, no. 6 (December 4, 2017): 514–21. http://dx.doi.org/10.1136/jclinpath-2017-204829.
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AimsWe investigated the clinical and prognostic relevance of the mutational status of driver genes with allele burden and endogenous erythroid colony (EEC) growth in 203 Taiwanese patients with primary myelofibrosis (PMF).MethodsPyrosequencing was used to detect JAK2V617F mutational status and measure allele burden, while MPL (exon 10) mutations were analysed by PCR assay and then by direct sequencing. CALR exon 9 mutations were first screened for length changes by GeneScan followed by sequencing. The allele burden of the mutated CALR gene was measured by pyrosequencing. The EEC assay was conducted using a serum-free culture system.ResultsThe frequencies of the three driver mutations and triple-negative status were similarly distributed between pre-PMF and overt PMF patients, except that pre-PMF patients had a higher incidence of CALR type 2/type-2 like mutations and a lower JAK2V617F allele burden. EEC growth and CALR mutations conferred favourable overall survival (OS). A lower JAK2V617F allele burden and grade 3 bone marrow fibrosis were associated with shorter OS and decreased leukaemia-free survival (LFS). Type 2/type 2-like CAL mutations were associated with better LFS compared with type1/type 1-like mutations. Patients with triple-negative mutation status had significantly worse OS and LFS. The allele burden of CALR mutations remained unchanged, while some JAK2V617F mutations showed clonal expansion in patients during secondary acute myeloid leukaemia transformation.ConclusionsOur study showed that EEC growth, a higher JAK2V617F allele burden and CALR mutations, especially type 2, were independent predictors for better outcomes in PMF. The allele burden of CALR mutations remained stable, but the allele burden of JAK2V617Fmutations was variable during leukaemia transformation.
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Kirschner, Martin, Monica Sofia Ventura Ferreira, Anne-Sophie Bouillon, Marcin W. Wlodarski, Michaela Schwarz, Stefan Balabanov, Stefan Wilop, et al. "Androgen Derivatives Improve Blood Counts and Elongate Telomere Length in Patients with Dyskeratosis Congenita." Blood 132, Supplement 1 (November 29, 2018): 2585. http://dx.doi.org/10.1182/blood-2018-99-118197.
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Abstract Introduction: Classical Dyskeratosis Congenita (DKC) is a systemic disorder characterized mainly by mucocutaneous features and bone marrow failure. DKC is caused by mutations affecting proper telomere maintenance leading to premature telomere shortening. Clinically, assessment of telomere length (TL) is being used for screening and diagnosis of DKC. Previous studies showed that androgen derivatives (AD) such as danazol or oxymetholone can improve blood counts and reduce transfusion frequency in patients with DKC. Reports from in vitro studies suggest that AD can increase the expression of telomerase and elongate telomeres reversing at least partially the mutation-related haploinsufficiency of the telomerase complex. However, whether telomere elongation can be observed in vivo is still controversial. Patients with DKC have an increased risk of developing solid tumors and acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Malignant transformation occurs mostly by chromosomal instability mediated by critical short telomeres and not via clonal hematopoiesis (CHIP) and eventual selection for MDS-related somatic mutations. The question whether increased telomerase activity by AD increases the risk for additional MDS-related mutations is unclear. In our study, we aimed to investigate TL and MDS-related somatic mutations in DKC patients undergoing treatment with AD. Methods and Patients: 5 patients enrolled in the Aachen Telomeropathy Registry (ATR) that underwent AD treatment were included in the analysis. All patients had molecularly confirmed DKC (4 patients having mutations in TERC, 1 patient in TERT). TERC mutated patients received danazol treatment (mean dosage 625 mg per day) while the patient with TERT mutation was treated with low dose oxymetholone (0.22mg/kg) per day. Patients were at a median age of 43.1 (range from 21.7 to 53.8) years. Median duration of treatment with AD was 14 months (3 to 29 mo) and is actually ongoing in all patients treated with danazol. Follow-up for blood counts and TL length assessment was carried out after median 14 months after treatment start with AD. TL assessment and blood counts of the patient receiving oxymetholone was carried out at the end of AD treatment after 29 months. All patients underwent next-generation sequencing (NGS) analysis using custom NGS-panel including frequent genes implicated in MDS development. Quality parameters of the NGS analysis were satisfactory (Q30>85%) and 95% of the expected area was covered at minimum 300x. To minimize risk of detecting sequencing errors, a threshold of 10 (absolute) and 5% (relative) variant allele frequency (VAF) was chosen. TL assessment of peripheral blood granulocytes and lymphocytes was carried out by Flow-FISH and all results are given in kb. Results: Analysis of the peripheral blood counts revealed a significant increase in platelets counts from mean 56/nl ±50 S.D. before treatment to 88/nl ±49 (p=0.03) during treatment. Similar results were observed for leukocyte counts increasing significantly from 3.83/µl±1.86 to 4.70/µl±2.88 (p=0.04). Hemoglobin counts showed a non-significant increase from 8.9 g/dl ±2.6 to 10.2 g/dl ±2.9 (p=0.13, all student paired t-test). Focusing on TL, lymphocyte TL increased significantly from 4.32kb±0.47 to 5.13kb ±0.57 (p=0.001). TL in the granulocyte subpopulation increased from 4.73kb±0.33 before treatment start to 6.10kb±0.50 under treatment (p=0.026). Calculated median increase in TL per months for lymphocytes and granulocytes was 0.092 kb (0.019 to 0.223 kb) and 0.166 kb (0.019kb to 0.513kb). Finally, NGS analysis for possible MDS-related mutations did not reveal any mutations before and under AD treatment. Conclusions: Based on our data in this genetically homogenous cohort of 5 patients with mutations in the telomerease genes TERC and TERT and short TL, AD significantly improve blood counts and elongate telomeres in granulocytes and lymphocytes. No MDS-related somatic mutations were observed during telomerase activation with AD. Pending longer follow up, treatment with AD seems to represent an efficient and safe therapy for patients with TERT or TERC mutations. Whether AD persistently elongate telomeres in DKC patients and how much this is dependent on the underlying DKC-related mutation requires further investigation. Disclosures Kirschner: Basilea Pharmaceutica: Other: travel support; BMS: Consultancy; Bayer: Consultancy; Roche: Consultancy. Wilop:Medizinwelten-Services GmbH: Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria, Other: Travel grant; Bristol-Myers Squibb: Honoraria. Brümmendorf:Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Novartis: Consultancy, Research Funding; Takeda: Consultancy; Merck: Consultancy. Beier:Gilead: Other: travel support; Celgene: Other: travel support.
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Takahashi, Noriko, Shino Mizuno, Takanori Hirano, Fabienne F. V. Chevance, Kelly T. Hughes, and Shin-Ichi Aizawa. "Autonomous and FliK-Dependent Length Control of the Flagellar Rod in Salmonella enterica." Journal of Bacteriology 191, no. 20 (August 7, 2009): 6469–72. http://dx.doi.org/10.1128/jb.00509-09.
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ABSTRACT Salmonella flgG point mutations produce filamentous rod structures whose lengths are determined by FliK. FliK length variants produce rods with lengths proportional to the corresponding FliK molecular size, suggesting that FliK controls the length of not only the hook but also the rod by the same molecular mechanism.
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Vulliamy, Tom J., Anna Marrone, Stuart W. Knight, Amanda Walne, Philip J. Mason, and Inderjeet Dokal. "Mutations in dyskeratosis congenita: their impact on telomere length and the diversity of clinical presentation." Blood 107, no. 7 (April 1, 2006): 2680–85. http://dx.doi.org/10.1182/blood-2005-07-2622.
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AbstractThe two genes mutated in the bone marrow failure syndrome dyskeratosis congenita (DC) both encode components of the telomerase complex responsible for maintaining the ends of chromosomes in stem cells and in the germ line. In reviewing the mutation profile that is found in DC, we describe 9 novel mutations in the DKC1 gene and 3 novel TERC mutations responsible for the X-linked and autosomal dominant forms of the disease, respectively, but find that two thirds of the families do not have mutations in either of these genes. In a significant subset of these uncharacterized families, the index case presents with severe disease previously defined as the Hoyeraal Hreidarsson (HH) syndrome. The diverse clinical phenotype seen in patients with X-linked DC is not explained by the different amino acid substitutions: Presentation of the recurrent A353V substitution ranges from classic DC to the severe HH variant. However, we do see that patients with HH have significantly shorter telomeres than those with a relatively mild presentation. In the new families described with TERC mutations, there is further evidence of disease anticipation associated with shorter telomeres in the younger generations. This study highlights the considerable genetic and phenotypic diversity of DC.
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Lee, Hsin-Chen, Yau-Huei Wei, and Jen-Hung Yang. "Photoageing-associated mitochondrial DNA length mutations in human skin." Archives of Dermatological Research 287, no. 7 (September 1995): 641–48. http://dx.doi.org/10.1007/bf00371736.
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Benthaus, Tobias, Gudrun Mellert, Evelyn Zellmeier, Wolfgang Hiddemann, Karsten Spiekermann, and Annika Dufour. "A Rapid and Sensitive Method for Large-Scale Screening of CEBPA Mutations in AML Patients with Normal Karyotype." Blood 110, no. 11 (November 16, 2007): 3483. http://dx.doi.org/10.1182/blood.v110.11.3483.3483.
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Abstract In 45% of patients with de novo acute myeloid leukemia (AML) no cytogenetic abnormalities can be detected (normal karyotype AML, NK-AML). Recently, several molecular markers with prognostic significance have been described which define distinct subgroups of NK-AML patients. Mutations in the CEBPA gene have shown to occur at about 8% of NK-AML in Western countries and confer a favorable prognosis. The C/EBPα protein, a member of the family of basic region leucine zipper (bZIP) transcriptional regulators, is important for normal granulocytic differentiation and is frequently disrupted in AML. We retrospectively analyzed bone-marrow samples of 442 patients with de novo NK-AML for the presence of CEBPA mutations and established a fast and sensitive screening method. A multiplex-PCR-gene scanning assay for combined detection of CEBPA and NPM mutation has recently been described in which, however, the primers did not cover the whole CEBPA gene. CEBPA mutations have been found to be distributed over the entire CEBPA gene and their functional and clinical consequences are not yet clear. Therefore, we designed a rapid CEBPA specific multiplex PCR-gene scanning assay covering the entire coding region of the CEBPA gene. Four primer pairs were designed, fluorescently labeled and included in 2 multiplex PCR reactions. The PCR products were electrophoresed on a genetic analyzer and the amplicon sizes were compared to wildtype CEBPA of U937 cell line by fragment length analysis. In order to evaluate our method, we analyzed 120 patient samples in parallel by both multiplex PCR and sequencing analysis. Using sequencing analysis as a gold standard, all of the CEBPA mutations could be detected by multiplex PCR and fragment length analysis. Thus, our multiplex PCR assay reached a sensitivity of 100%. The specificity was 89% due to the false positive detection of a 6 basepair duplication polymorphism in 2.5% of patients (Wouters BJ et al, Blood, 2007). 322 patient samples were subsequently screened for CEBPA mutations by the multiplex PCR assay. In case of alterations in the fragment length analysis, the relevant CEBPA region was sequenced to identify the exact type of mutation. Among 442 patients with NK-AML, 32 patients (7%) showed CEBPA mutations. Taken together, we identified 47 mutations in 32 patients, of which 17 patients had a single CEBPA mutation and 15 patients had more than one CEBPA mutation. We identified 30 out of frame insertion/deletion nonsense mutations resulting in an N-terminal stopcodon and 14 in frame insertion/deletion mutations as well as 3 out of frame insertion/deletion mutations in the C-terminal bZIP region. The only limitation of this method might be that single basepair substitutions, which do not affect the length of the amplicon, cannot be detected. Substitutions in the CEBPA gene are, however, rare events and often silent. In 120 sequenced AML patients we did not find any non-silent substitution. We established a fast and sensitive screening method suitable for large-scale detection of CEBPA mutation and applicable for inclusion in routine AML diagnostics. This is so far the largest reported analysis of CEBPA mutations in patients with NK-AML and might provide further insights into the functional and clinical relevance of the different types of CEBPA mutations and their correlation to other molecular markers in NK-AML.
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Gao, Feng, Yalu Chen, David N. Levy, Joan A. Conway, Thomas B. Kepler, and Huxiong Hui. "Unselected Mutations in the Human Immunodeficiency Virus Type 1 Genome Are Mostly Nonsynonymous and Often Deleterious." Journal of Virology 78, no. 5 (March 1, 2004): 2426–33. http://dx.doi.org/10.1128/jvi.78.5.2426-2433.2004.
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ABSTRACT Mutation rates of human immunodeficiency virus type 1 (HIV-1) genomes have been estimated using purified reverse transcriptase or single-round infection system. Since small sequences were used as templates, the overall mutation rates could only be extrapolated and the biological significance of mutations is unknown. For direct estimation of HIV-1 mutation rates and understanding of the potential biological influences of mutations, we obtained 19 complete or nearly full-length proviral genomes from single-round-infected adherent cells of lymphocytes by using a lambda phage library method and a long-range PCR technique. Analysis of 160,000 bp of sequences showed that the overall mutation rate of HIV-1 genomes was 5.4 × 10−5 per base per replication cycle. On average, 1.1 mutations (range, 0 to 3) were generated in each viral genome during one infection cycle. Inspection of the mutations in the HIV-1 genome revealed that all site mutations within protein-coding regions were nonsynonymous mutations. Among all mutations, half were deleterious (premature stop codon and deletions) and would result in defective genomes. By applying the same system to an HIV-1 genome with a G262A mutation in the thumb region of the reverse transcriptase, a significant increase was observed in deletion and insertion mutation rates but no increase in the overall mutation rate in viral genomes was found.
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Ruan, Zheng, and Natarajan Kannan. "Altered conformational landscape and dimerization dependency underpins the activation of EGFR by αC–β4 loop insertion mutations." Proceedings of the National Academy of Sciences 115, no. 35 (August 13, 2018): E8162—E8171. http://dx.doi.org/10.1073/pnas.1803152115.
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Mutational activation of epidermal growth factor receptor (EGFR) in human cancers involves both point mutations and complex mutations (insertions and deletions). In particular, short in-frame insertion mutations within a conserved αC–β4 loop in the EGFR kinase domain are frequently observed in tumor samples and patients harboring these mutations are insensitive to first-generation EGFR inhibitors. Despite the prevalence and clinical relevance of insertion mutations, the mechanisms by which these mutations regulate EGFR activity and contribute to drug sensitivity are poorly understood. Using cell-based mutation screening, we find that the precise location, length, and sequence of the inserted segment are critical for ligand-independent EGFR activation and downstream signaling. We identify three insertion mutations (N771_P772insN, D770_N771insG, and D770>GY) that activate EGFR in a unique way by relying more on the “acceptor” interface for kinase activation. Our drug inhibition studies indicate that these activating insertion mutations respond more favorably to osimertinib, a recently Food and Drug Administration-approved EGFR inhibitor for T790M-positive patients with lung cancer. Molecular dynamics simulations and umbrella sampling of WT and mutant EGFR suggest a model in which activating insertion mutations increase catalytic activity by relieving key autoinhibitory interactions associated with αC-helix movement and by lowering the transition free energy (ΔGactive-inactive) between active and inactive states. Our studies also identify a transition state sampled by activating insertion mutations that can be exploited in the design of mutant-selective EGFR inhibitors.
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Zubkova, Natalia A., Fatima F. Burumkulova, Victoria I. Ulyatovskaya, Vasily A. Petrukhin, Margarita A. Plechanova, Anton E. Panov, Tatiana S. Budykina, Nina A. Makretskaya, and Anatoly N. Tiulpakov. "Birth weight and length in offsprings of mothers with gestational diabetes mellitus due to mutations in GCK gene." Diabetes mellitus 21, no. 2 (May 21, 2018): 92–98. http://dx.doi.org/10.14341/dm9429.
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Background. Gestational diabetes (GDM) due to GCK gene mutations is the most frequent form of monogenic diabetes mellitus (DM) presenting during pregnancy. It has been suggested that the use of insulin in pregnancies with fetuses carrying GCK mutations may lead to intrauterine growth retardation. In the present study we evaluated the effect of insulin therapy during pregnancy on birth weight and length in the offsprings of mothers with GDM due to GCK mutations.
Aims. The aim was to study birth weight and length in offsprings of mothers with gestational diabetes mellitus due to mutations in GCK, depending on the therapy during pregnancy.
Materials and methods. The study included 38 patients with GDM caused by GCK gene mutations (18.7%) and the 45 offsprings. To define molecular basis of GDM in pregnant women we used a targeted NGS. Diabetes panel genes were sequenced using a custom Ion Ampliseq gene panel and PGM semiconductor sequencer (Ion Torrent). To found the same mutations in their offsprings was used Sanger sequencing. All children were divided into 3 groups depending of their genotype and therapy received by the mothers during pregnancy.
Results. We found statistically significant differences in birth length (p=0.04) and weight (p=0,031) depending on the genotype of the child and therapy in the mother. The risk of macrosomia was shown in non-mutation-carrying offsprings only. The birth weight in children with GCK gene mutations whose mothers received insulin during pregnancy was significantly lower. However, the birth weight remained in the normal range.
Conclusions. Since prenatal diagnostics in the mothers with GCK gene mutations is not always justified, we recommend insulin therapy in order to prevent fetal macrosomia, which, however, should be less aggressive than in GDM due to other causes.
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Vempati, Sridhar, Ruth Schwab, Theodora Malamoussi, Martin Dugas, Gudrun Mellert, Susanne Schnittger, Wolfgang Hiddemann, and Karsten Spiekermann. "Arginine (R) at Position 595 in FLT3 Is Critical for Transforming Potential of FLT3-Length Mutations." Blood 106, no. 11 (November 16, 2005): 1598. http://dx.doi.org/10.1182/blood.v106.11.1598.1598.
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Abstract Activating mutations in the juxtamembrane region of FMS-like tyrosine kinase-3 (FLT3-length mutations, FLT3-LM)-are found in 20–25% of patients with acute myeloid leukemia (AML). FLT3-LM consists of duplications and additional insertions that show a variable length and site of insertion. Although these different length mutations lead to constitutive activation of FLT3 and subsequent downstream signalling pathways, several questions still remain unanswered. Here, we focussed on the question whether a common sequence motif in the duplicated region can be identified in patients carrying FLT3-LM. To address this topic we sequenced the juxtamembrane region of FLT3 from 274 patients with acute leukemias. We found that the length of mutation (tandem duplications) varied from 2–42 amino acids with a median of 17 AA. Furthermore, the duplicated amino acids centered around the motif DFREYEY of FLT3. Since the length of the motif DFREYEY varied from patient to patient, we focussed our study on the frequency of single amino acids within the duplicated region. We found that arginine (R) 595 in the motif DFREYEY is duplicated in 77% of patients. Further studies showed that a single duplication of arginine at position 595 in FLT3 is able to confer factor independent growth to Ba/F3 cells. In vitro, deletion or substitution of duplicated R 595 in two FLT3-LMs with different lengths showed a 50% reduction in the factor independent growth when compared to undeleted/non-substituted FLT3-LMs. The reduced proliferative capacity of Ba/F3 cells expressing FLT3-LM with deletions of R-595 was associated with a reduction of STAT5 activation. Our data provide important insights into the molecular mechanisms of transformation by FLT3-LM and define duplicated R 595 as a critical mediator of the leukemic potential of these mutants.
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Cue, David, and Michael Feiss. "Genetic Evidence That Recognition of cosQ the Signal for Termination of Phage λ DNA Packaging, Depends on the Extent of Head Filling." Genetics 147, no. 1 (September 1, 1997): 7–17. http://dx.doi.org/10.1093/genetics/147.1.7.
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Abstract Packaging a phage λ chromosome involves cutting the chromosome from a concatemer and translocating the DNA into a prohead. The cutting site, cos, consists of three subsites: cosN, the nicking site; cosB, a site required for packaging initiation; and cosQ a site required for termination of packaging. cosB contains three binding sites (R sequences) for gpNul, the small subunit of terminase. Because cosQ has sequence identity to the R sequences, it has been proposed that cosQ is also recognized by gpNul. Suppressors of cosB mutations were unable to suppress a cosQ point mutation. Suppressors of a cosQ mutation (cosQ1) were isolated and found to be of three sorts, the first affecting a base pair in cosQ. The second type of cosQ suppression involved increasing the length of the phage chromosome to a length near to the maximum capacity of the head shell. A third class of suppressors were missense mutations in gene B, which encodes the portal protein of the virion. It is speculated that increasing DNA length and altering the portal protein may reduce the rate of translocation, thereby increasing the efficiency of recognition of the mutant cosQ. None of the cosQ suppressors was able to suppress cosB mutations. Because cosQ and cosB mutations are suppressed by very different types of suppressors, it is concluded that cosQ and the R sequences of cosB are recognized by different DNA-binding determinants.
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Gutierrez-Rodrigues, Fernanda, Gustavo Borges, Raquel M. Alves-Paiva, Bárbara A. Santana-Lemos, Samantha Nichele, Lisandro L. Ribeiro, Michel Michels De Oliveira, et al. "Telomere Biology Gene Mutation and Transplant Outcome in Patients with Dyskeratosis Congenita." Blood 126, no. 23 (December 3, 2015): 4785. http://dx.doi.org/10.1182/blood.v126.23.4785.4785.
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Abstract Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome known as the prototype of telomere diseases. In addition to the clinical triad (nail dystrophy, hyperpigmentation, and leukoplakia), very short telomeres (below the 1st percentile) is a marker for the diagnosis of DC (Calado & Young, NEJM 2009). Telomere dysfunction was associated with DC after discovery of DKC1 mutations in patients presenting the X-linked form of the syndrome. Novel mutations in telomere biology genes (TERC, TERT, NOP10, NHP2, TINF2, TCAB1, CTC1, RTEL1, ACD, and PARN) have been described in patients with DC. Variations in all these genes can affect telomere protection and maintenance, leading to telomere shortening and development of telomeropathies. In this study, we mapped the TERT, TERC, DKC1, and TINF2 genes for mutations in 15 patients (median age = 10 years; M/F = 11/4) with DC and very short telomeres, in order to classify these cases in a molecular level and determine the frequency of these mutations in our cohort. Survival for twelve patients who underwent allogeneic hematopoietic stem cell transplant (HSCT) was assessed and correlated with mutational status and telomere length. Diagnosis of DC was made according to the definition of Calado & Young (2009). Telomere length was measured in nucleated blood cells by flow-FISH and mutational screening was performed on genomic DNA extracted from peripheral blood cells by direct sequencing. Seven non-synonymous mutations were identified in TINF2 (40%), two in DKC1 (13%), one in TERT (6%), and one in TERC (6%). The TINF2 variants R282H and R282C had been already described as pathogenic, as well T66A and A353V DKC1 variants (Knight et al, 1999; Savage et al, 2008; Walne et al, 2008). The heterozygous variant R282H (c. 845 G>A) in TINF2 were found in 4 unrelated patients. One of them also harbor the variants Q120R and Q157H in the same gene. The heterozygous mutation in TINF2 R282C (c. 844 C>T) was found in one patient, that also presented the common polymorphism A279T in TERT. The pathogenic variants T66A (c.196A>G) and A353V (c.1058C>T) in DKC1 were found in two different male patients. Moreover, three novel mutations were identified in our cohort, r.94 C>T in TERC, F290C in TINF2, and R696Cin TERT. The heterozygous mutation r.94 (C>T) found in TERC was located at the pseudoknot P2b region of the gene and the patient who carries that presented a severe aplastic anemia and all DC clinical triad. The novel heterozygous F290C (c.859 T>G) variant is located at the "hot spot" in exon 6 of TINF2 andwas found in one patient that presented a severe phenotype of DC. In silico analysis with SIFT and Polyphen-2 predicted that this variant is not tolerated and probably damaging, which is consistent with the pathogenicity of the mutation. The homozygous mutation R696C (c.2086 C>T) in TERT was found in one patient and also in his two brothers. All of them presented reduced blood cell count, clinical features of DC, and severe aplastic anemia. The family screening identified the father and sister as heterozygous for the same mutation, but both asymptomatic. DNA sample from the mother were not available for this study. In silico analysis by SIFT and Polyphen 2.0, predicted that the R696C mutation is not tolerant and possible damaging to telomerase activity, respectively. To validate in silico analysis, TRAP assay with cell lysates obtained from telomerase-negative VA13 cell line transfected with wild type or R696C mutated TERT vector and TERC vector is under evaluation. Consistently with previously studies, telomere length in patients with TINF2 mutations were the shortest compared with the other telomeres genes mapped in this study. Although, the phenotype and severity of the disease does not appear to change according to the mutated gene. Also, the mutational status (p=0.28) or telomere length (p=0.21) did not influence the survival rates of patients after HSCT. Flow-FISH was able to identify patients with very short telomeres and validated telomere length measurement as a diagnostic tool for DC. Direct sequencing of the most commonly mutated genes in DC in a cohort of patients with telomeres below 1st percentile was able to characterize the genetic cause of this disease in more than 70% of the cases. The identification of genetic defect in DC can manage clinical decisions and is essential to genetic counseling prior to bone marrow transplantation. Disclosures No relevant conflicts of interest to declare.
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Weyerer, Veronika, Markus Eckstein, Pamela L. Strissel, Adrian Wullweber, Fabienne Lange, Lars Tögel, Carol I. Geppert, et al. "TERT Promoter Mutation Analysis of Whole-Organ Mapping Bladder Cancers." Genes 12, no. 2 (February 5, 2021): 230. http://dx.doi.org/10.3390/genes12020230.
Full textAbstract:
Background: Multifocal occurrence is a main characteristic of urothelial bladder cancer (UBC). Whether urothelial transformation is caused by monoclonal events within the urothelium, or by polyclonal unrelated events resulting in several tumor clones is still under debate. TERT promoter mutations are the most common somatic alteration identified in UBC. In this study, we analyzed different histological tissues from whole-organ mapping bladder cancer specimens to reveal TERT mutational status, as well as to discern how tumors develop. Methods: Up to 23 tissues from nine whole-organ mapping bladder tumor specimens, were tested for TERT promoter mutations including tumor associated normal urothelium, non-invasive urothelial lesions (hyperplasia, dysplasia, metaplasia), carcinoma in situ (CIS) and different areas of muscle invasive bladder cancers (MIBC). The mutational DNA hotspot region within the TERT promoter was analyzed by SNaPshot analysis including three hot spot regions (−57, −124 or −146). Telomere length was measured by the Relative Human Telomere Length Quantification qPCR Assay Kit. Results: TERT promoter mutations were identified in tumor associated normal urothelium as well as non-invasive urothelial lesions, CIS and MIBC. Analysis of separate regions of the MIBC showed 100% concordance of TERT promoter mutations within a respective whole-organ bladder specimen. Polyclonal events were observed in five out of nine whole-organ mapping bladder cancers housing tumor associated normal urothelium, non-invasive urothelial lesions and CIS where different TERT promoter mutations were found compared to MIBC. The remaining four whole-organ mapping bladders were monoclonal for TERT mutations. No significant differences of telomere length were observed. Conclusions: Examining multiple whole-organ mapping bladders we conclude that TERT promoter mutations may be an early step in bladder cancer carcinogenesis as supported by TERT mutations detected in tumor associated normal urothelium as well as non-invasive urothelial lesions. Since mutated TERT promoter regions within non-invasive urothelial lesions are not sufficient alone for the establishment of cancerous growth, this points to the contribution of other gene mutations as a requirement for tumor development.
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Lambert, I. B., A. J. Gordon, B. W. Glickman, and D. R. McCalla. "The influence of local DNA sequence and DNA repair background on the mutational specificity of 1-nitroso-8-nitropyrene in Escherichia coli: inferences for mutagenic mechanisms." Genetics 132, no. 4 (December 1, 1992): 911–27. http://dx.doi.org/10.1093/genetics/132.4.911.
Full textAbstract:
Abstract We have examined the mutational specificity of 1-nitroso-8-nitropyrene (1,8-NONP), an activated metabolite of the carcinogen 1,8-dinitropyrene, in the lacI gene of Escherichia coli strains which differ with respect to nucleotide excision repair (+/- delta uvrB) and MucA/B-mediated error-prone translesion synthesis (+/- pKM101). Several different classes of mutation were recovered, of which frameshifts, base substitutions, and deletions were clearly induced by 1,8-NONP treatment. The high proportion of point mutations (> 92%) which occurred at G.C sites correlates with the percentage of 1,8-NONP-DNA adducts which occur at the C(8) position of guanine. The most prominent frameshift mutations were -(G.C) events, which were induced by 1,8-NONP treatment in all strains, occurred preferentially in runs of guanine residues, and whose frequency increased markedly with the length of the reiterated sequence. Of the base substitution mutations G.C-->T.A transversions were induced to the greatest extent by 1,8-NONP. The distribution of the G.C-->T.A transversions was not influenced by the nature of flanking bases, nor was there a strand preference for these events. The presence of plasmid pKM101 specifically increased the frequency of G.C-->T.A transversions by a factor of 30-60. In contrast, the -(G.C) frameshift mutation frequency was increased only 2-4-fold in strains harboring pKM101 as compared to strains lacking this plasmid. There was, however, a marked influence of pKM101 on the strand specificity of frameshift mutation; a preference was observed for -G events on the transcribed strand. The ability of the bacteria to carry out nucleotide excision repair had a strong effect on the frequency of all classes of mutation but did not significantly influence either the overall distribution of mutational classes or the strand specificity of G.C-->T.A transversions and -(G.C) frameshifts. Deletion mutations were induced in the delta uvr, pKM101 strain. The endpoints of the majority of the deletion mutations were G.C rich and contained regions of considerable homology. The specificity of 1,8-NONP-induced mutation suggests that DNA containing 1,8-NONP adducts can be processed through different mutational pathways depending on the DNA sequence context of the adduct and the DNA repair background of the cell.