Somatic<i>POLE</i>mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis

Erson‐Omay, E. Zeynep; Çağlayan, Ahmet Okay; Schultz, Nikolaus; Weinhold, Nils; Omay, Sacit Bulent; Özduman, Koray; Köksal, Yavuz; Li, Jie; Harmancı, Akdes Serin; Clark, Victoria; Carrión-Grant, Geneive; Baranoski, Jacob F; Çağlar, Caner; Barak, Tanyeri; Suleyman, Coskun; Baran, Burçin; Köse, Doğan; Sun, Jia; Bakırcıoğlu, Mehmet; Günel, Jennifer Moliterno; Pamir, M. Necmettin; Mishra-Gorur, Ketu; Bilgüvar, Kaya; Yasuno, Katsuhito; Vortmeyer, Alexander O.; Hüttner, Anita; Sander, Chris; Günel, Murat

doi:10.1093/neuonc/nov027

Cited by 96 publications

(82 citation statements)

References 45 publications

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“…Similar asymmetry patterns in samples with inactivating mutations in MMR system and Pol epsilon were observed in other available cancer data sets: whole genomes of uterine corpus endometrial carcinoma (UCEC) and colon adenocarcinoma (COAD), as well as in another independent data set of bMMRD glioblastoma cancers (Supplemental Figs. S4-S6;Erson-Omay et al 2015). Moreover, these trends are consistent between individual samples (Supplemental Table S3), which shows that this asymmetry is specific to the mutational processes rather than cancer sample or cancer type.…”

Section: Stand-specific Mutational Patterns In Cancers With Mutated Psupporting

confidence: 56%

“…In these patients, the fidelity of the damaged polymerase is decreased by a factor of 100 to 1000, and most mutations are produced by it (Korona et al 2011;Henninger and Pursell 2014;Erson-Omay et al 2015;Shlien et al 2015). We found that the relative frequencies of mutation types were distorted in these cancers compared with tumors without mutations in polymerases (Fig.…”

Section: Stand-specific Mutational Patterns In Cancers With Mutated Pmentioning

confidence: 72%

“…We used the following previously published data: (1) somatic mutations for whole-exome sequences of MSI (n = 159) and MSS (n = 782) cancers and for whole-genome sequences of MSI (n = 11) and MSS (n = 27) cancers from the data portal of The Cancer Genome Atlas (TCGA; https://portal.gdc.cancer.gov/); (2) BAM files with aligned reads for ultra-hypermutated cancers with inherited bMMRD and somatic mutation in Pol epsilon or Pol delta (Shlien et al 2015); (3) VCF files for hypermutated cancers with inherited homozygous mutation in the MSH2 gene (MMR system) and somatic mutation in Pol epsilon (Erson-Omay et al 2015); (4) human-chimpanzee-orangutan multiple alignment from the UCSC Genome Browser (https://genome.ucsc.edu/); and (5) human polymorphism data from 1000 Genomes Project. Substitution rates were calculated as the number of substitutions of a particular type divided by the number of target sites.…”

Section: Mutation Datamentioning

confidence: 99%

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Human mismatch repair system balances mutation rates between strands by removing more mismatches from the lagging strand

et al. 2017

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Mismatch repair (MMR) is one of the main systems maintaining fidelity of replication. Differences in correction of errors produced during replication of the leading and the lagging DNA strands were reported in yeast and in human cancers, but the causes of these differences remain unclear. Here, we analyze data on human cancers with somatic mutations in two of the major DNA polymerases, delta and epsilon, that replicate the genome. We show that these cancers demonstrate a substantial asymmetry of the mutations between the leading and the lagging strands. The direction of this asymmetry is the opposite between cancers with mutated polymerases delta and epsilon, consistent with the role of these polymerases in replication of the lagging and the leading strands in human cells, respectively. Moreover, the direction of strand asymmetry observed in cancers with mutated polymerase delta is similar to that observed in MMR-deficient cancers. Together, these data indicate that polymerase delta (possibly together with polymerase alpha) contributes more mismatches during replication than its leading-strand counterpart, polymerase epsilon; that most of these mismatches are repaired by the MMR system; and that MMR repairs about three times more mismatches produced in cells during lagging strand replication compared with the leading strand.

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Section: Stand-specific Mutational Patterns In Cancers With Mutated Psupporting

confidence: 56%

Section: Stand-specific Mutational Patterns In Cancers With Mutated Pmentioning

confidence: 72%

Section: Mutation Datamentioning

confidence: 99%

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Human mismatch repair system balances mutation rates between strands by removing more mismatches from the lagging strand

et al. 2017

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“…Somatic and germline POLE mutations have been identified in a number of different cancers, including endometrial, colorectal, and giant cell high-grade glioma (10,(13)(14)(15)(16). POLE encodes the DNA polymerase epsilon, which is responsible for leading strand DNA replication (17,18).…”

Section: Introductionmentioning

confidence: 99%

Endometrial Carcinomas with POLE Exonuclease Domain Mutations Have a Favorable Prognosis

McConechy

Talhouk

Leung

et al. 2016

Clinical Cancer Research

145

109

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Purpose: The aim of this study was to confirm the prognostic significance of POLE exonuclease domain mutations (EDM) in endometrial carcinoma patients. In addition, the effect of treatment on POLE-mutated tumors was assessed.Experimental Design: A retrospective patient cohort of 496 endometrial carcinoma patients was identified for targeted sequencing of the POLE exonuclease domain, yielding 406 evaluable tumors. Univariable and multivariable analyses were performed to determine the effect of POLE mutation status on progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS). Combining results from eight studies in a meta-analysis, we computed pooled HR for PFS, DSS, and OS.Results: POLE EDMs were identified in 39 of 406 (9.6%) endometrial carcinomas. Women with POLE-mutated endometrial carcinomas were younger, with stage I (92%) tumors, grade 3 (62%), endometrioid histology (82%), and frequent (49%) lymphovascular invasion. In univariable analysis, POLE-mutated endometrial carcinomas had significantly improved outcomes compared with patients with no EDMs for PFS, DSS, and OS. In multivariable analysis, POLE EDMs were only significantly associated with improved PFS. The effect of adjuvant treatment on POLE-mutated cases could not be determined conclusively; however, both treated and untreated patients with POLE EDMs had good outcomes. Meta-analysis revealed an association between POLE EDMs and improved PFS and DSS with pooled HRs 0.34 [95% confidence interval (CI), 0.15-0.73] and 0.35 (95% CI, 0.13-0.92), respectively.Conclusions: POLE EDMs are prognostic markers associated with excellent outcomes for endometrial carcinoma patients. Further investigation is needed to conclusively determine if treatment is necessary for this group of women.

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“…Most brain tumors are malignant gliomas, although low-grade lesions have been observed. The morphologic features of these gliomas include large, multinucleated giant cells with clumped nuclei and cells with many smaller, eccentrically placed nuclei mimicking pleomorphic xanthroastrocytomas (13). Central nervous system (CNS) embryonal tumors and medulloblastomas have also been reported (11,14).…”

Section: Clinical Presentation Of Cmmrdmentioning

confidence: 99%

Clinical Management and Tumor Surveillance Recommendations of Inherited Mismatch Repair Deficiency in Childhood

Tabori

Hansford

Achatz

et al. 2017

Clinical Cancer Research

158

186

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Replication proofreading is crucial to avoid mutation accumulation in dividing cells. In humans, proofreading and replication repair is maintained by the exonuclease domains of DNA polymerases and the mismatch repair system. Individuals harboring germline mutations in genes involved in this process are at increased risk of early cancers from multiple organs. Biallelic mutations in any of the four mismatch repair genes MSH2, MSH6, MLH1, and PMS2 result in one of the most aggressive childhood cancer predisposition syndromes, termed constitutional mismatch repair deficiency or constitutional mismatch repair deficiency syndrome (CMMRD). Data gathered in the last decade allow us to better define the clinical manifestations, tumor spectrum, and diagnostic algorithms for CMMRD. In this article, we summarize this information and present a comprehensive consensus surveillance protocol for these individuals. Ongoing research will allow for further definition of replication repairdeficient cancer syndromes, assessing the cost-effectiveness of such surveillance protocols and potential therapeutic interventions for these children and families. Clin Cancer Res; 23(11); e32-e37. Ó2017 AACR.See all articles in the online-only CCR Pediatric Oncology Series.

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SomaticPOLEmutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis

Cited by 96 publications

References 45 publications

Human mismatch repair system balances mutation rates between strands by removing more mismatches from the lagging strand

Human mismatch repair system balances mutation rates between strands by removing more mismatches from the lagging strand

Endometrial Carcinomas with POLE Exonuclease Domain Mutations Have a Favorable Prognosis

Clinical Management and Tumor Surveillance Recommendations of Inherited Mismatch Repair Deficiency in Childhood

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