Molecular profiling and sequential somatic mutation shift in hypermutator tumours harbouring POLE mutations.
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ABSTRACT:
SUBMITTER: Hatakeyama K
PROVIDER: S-EPMC5992218 | biostudies-literature | 2018 Jun
REPOSITORIES: biostudies-literature
Publications
Molecular profiling and sequential somatic mutation shift in hypermutator tumours harbouring POLE mutations.
Hatakeyama Keiichi K Ohshima Keiichi K Nagashima Takeshi T Ohnami Shumpei S Ohnami Sumiko S Serizawa Masakuni M Shimoda Yuji Y Maruyama Koji K Akiyama Yasuto Y Urakami Kenichi K Kusuhara Masatoshi M Mochizuki Tohru T Yamaguchi Ken K
Scientific reports 20180607 1
Defective DNA polymerase ε (POLE) proofreading leads to extensive somatic mutations that exhibit biased mutational properties; however, the characteristics of POLE-mutated tumours remain unclear. In the present study, we describe a molecular profile using whole exome sequencing based on the transition of somatic mutations in 10 POLE-mutated solid tumours that were obtained from 2,042 Japanese patients. The bias of accumulated variations in these mutants was quantified to follow a pattern of soma ...[more]
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Project description:Pathogenic somatic missense mutations within the DNA polymerase epsilon (POLE) exonuclease domain define the important subtype of ultramutated tumours ('POLE-ultramutated') within the novel molecular classification of endometrial carcinoma (EC). However, clinical implementation of this classifier requires systematic evaluation of the pathogenicity of POLE mutations. To address this, we examined base changes, tumour mutational burden (TMB), DNA microsatellite instability (MSI) status, POLE variant frequency, and the results from six in silico tools on 82 ECs with whole-exome sequencing from The Cancer Genome Atlas (TCGA). Of these, 41 had one of five known pathogenic POLE exonuclease domain mutations (EDM) and showed characteristic genomic alterations: C>A substitution > 20%, T>G substitutions > 4%, C>G substitutions < 0.6%, indels < 5%, TMB > 100 mut/Mb. A scoring system to assess these alterations (POLE-score) was developed; based on their scores, 7/18 (39%) additional tumours with EDM were classified as POLE-ultramutated ECs, and the six POLE mutations present in these tumours were considered pathogenic. Only 1/23 (4%) tumours with non-EDM showed these genomic alterations, indicating that a large majority of mutations outside the exonuclease domain are not pathogenic. The infrequent combination of MSI-H with POLE EDM led us to investigate the clinical significance of this association. Tumours with pathogenic POLE EDM co-existent with MSI-H showed genomic alterations characteristic of POLE-ultramutated ECs. In a pooled analysis of 3361 ECs, 13 ECs with DNA mismatch repair deficiency (MMRd)/MSI-H and a pathogenic POLE EDM had a 5-year recurrence-free survival (RFS) of 92.3%, comparable to previously reported POLE-ultramutated ECs. Additionally, 14 cases with non-pathogenic POLE EDM and MMRd/MSI-H had a 5-year RFS of 76.2%, similar to MMRd/MSI-H, POLE wild-type ECs, suggesting that these should be categorised as MMRd, rather than POLE-ultramutated ECs for prognostication. This work provides guidance on classification of ECs with POLE mutations, facilitating implementation of POLE testing in routine clinical care. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Project description:BackgroundGastric cancer is one of the leading cancer types in incidence and mortality, especially in Asia. In order to improve survival, identification of a catalogue of molecular alterations underlying gastric cancer is a critical step for developing and designing genome-directed therapies.Methodology/principal findingsThe Center for Cancer Genome Discovery (CCGD) at the Dana-Farber Cancer Institute (DFCI) has adapted a high-throughput genotyping platform to determine the mutation status of a large panel of known cancer genes. The mutation detection platform, termed OncoMap v4, interrogates 474 "hotspot" mutations in 41 genes that are relevant for cancer. We performed OncoMap v4 in formalin-fixed paraffin-embedded (FFPE) tissue specimens from 237 gastric adenocarcinomas. Using OncoMap v4, we found that 34 (14.4%) of 237 gastric cancer patients harbored mutations. Among mutations we screened, PIK3CA mutations were the most frequent (5.1%) followed by p53 (4.6%), APC (2.5%), STK11 (2.1%), CTNNB1 (1.7%), and CDKN2A (0.8%). Six samples harbored concomitant somatic mutations. Mutations of CTNNB1 were significantly more frequent in EBV-associated gastric carcinoma (P = 0.046). Our study led to the detection of potentially druggable mutations in gastric cancer which may guide novel therapies in subsets of gastric cancer patients.Conclusions/significanceUsing high throughput mutation screening platform, we identified that PIK3CA mutations were the most frequently observed target for gastric adenocarcinoma.
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