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Somatic mutations favorable to patient survival are predominant in ovarian carcinomas.

ABSTRACT: Somatic mutation accumulation is a major cause of abnormal cell growth. However, some mutations in cancer cells may be deleterious to the survival and proliferation of the cancer cells, thus offering a protective effect to the patients. We investigated this hypothesis via a unique analysis of the clinical and somatic mutation datasets of ovarian carcinomas published by the Cancer Genome Atlas. We defined and screened 562 macro mutation signatures (MMSs) for their associations with the overall survival of 320 ovarian cancer patients. Each MMS measures the number of mutations present on the member genes (except for TP53) covered by a specific Gene Ontology (GO) term in each tumor. We found that somatic mutations favorable to the patient survival are predominant in ovarian carcinomas compared to those indicating poor clinical outcomes. Specially, we identified 19 (3) predictive MMSs that are, usually by a nonlinear dose-dependent effect, associated with good (poor) patient survival. The false discovery rate for the 19 "positive" predictors is at the level of 0.15. The GO terms corresponding to these MMSs include "lysosomal membrane" and "response to hypoxia", each of which is relevant to the progression and therapy of cancer. Using these MMSs as features, we established a classification tree model which can effectively partition the training samples into three prognosis groups regarding the survival time. We validated this model on an independent dataset of the same disease (Log-rank p-value < 2.3 × 10(-4)) and a dataset of breast cancer (Log-rank p-value < 9.3 × 10(-3)). We compared the GO terms corresponding to these MMSs and those enriched with expression-based predictive genes. The analysis showed that the GO term pairs with large similarity are mainly pertinent to the proteins located on the cell organelles responsible for material transport and waste disposal, suggesting the crucial role of these proteins in cancer mortality.

SUBMITTER: Zhang W

PROVIDER: S-EPMC4229214 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Somatic mutations favorable to patient survival are predominant in ovarian carcinomas.

Zhang Wensheng W Edwards Andrea A Flemington Erik E Zhang Kun K

PloS one 20141112 11

Somatic mutation accumulation is a major cause of abnormal cell growth. However, some mutations in cancer cells may be deleterious to the survival and proliferation of the cancer cells, thus offering a protective effect to the patients. We investigated this hypothesis via a unique analysis of the clinical and somatic mutation datasets of ovarian carcinomas published by the Cancer Genome Atlas. We defined and screened 562 macro mutation signatures (MMSs) for their associations with the overall su ...[more]

PMID: 25390899

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Project description:Chemotherapy response in the majority of patients with ovarian cancer remains unpredictable.To identify novel molecular markers for predicting chemotherapy response in patients with ovarian cancer.Observational study of genomics and clinical data of high-grade serous ovarian cancer cases with genomic and clinical data made public between 2009 and 2014 via the Cancer Genome Atlas project.Chemotherapy response (primary outcome) and overall survival (OS), progression-free survival (PFS), and platinum-free duration (secondary outcome).In 512 patients with ovarian cancer with available whole-exome sequencing data, mutations from 8 members of the ADAMTS family (ADAMTS mutations) with an overall mutation rate of approximately 10.4% were associated with a significantly higher chemotherapy sensitivity (100% for ADAMTS-mutated vs 64% for ADAMTS wild-type cases; P?<?.001) and longer platinum-free duration (median platinum-free duration, 21.7 months for ADAMTS-mutated vs 10.1 months for ADAMTS wild-type cases; P?=?.001). Moreover, ADAMTS mutations were associated with significantly better OS (hazard ratio [HR], 0.54 [95% CI, 0.42-0.89]; P?=?.01 and median OS, 58.0 months for ADAMTS-mutated vs 41.3 months for ADAMTS wild-type cases) and PFS (HR, 0.42 [95% CI, 0.38-0.70]; P?<?.001 and median PFS, 31.8 for ADAMTS-mutated vs 15.3 months for ADAMTS wild-type cases). After adjustment by BRCA1 or BRCA2 mutation, surgical stage, residual tumor, and patient age, ADAMTS mutations were significantly associated with better OS (HR, 0.53 [95% CI, 0.32-0.87]; P?=?.01), PFS (HR, 0.40 [95% CI, 0.25-0.62]; P?<?.001), and platinum-free survival (HR, 0.45 [95% CI, 0.28-0.73]; P?=?.001). ADAMTS-mutated cases exhibited a distinct mutation spectrum and were significantly associated with tumors with a higher genome-wide mutation rate than ADAMTS wild-type cases across the whole exome (median mutation number per sample, 121 for ADAMTS-mutated vs 69 for ADAMTS wild-type cases; P?<?.001).ADAMTS mutations may contribute to outcomes in ovarian cancer cases without BRCA1 or BRCA2 mutations and may have important clinical implications.

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Somatic mutations favorable to patient survival are predominant in ovarian carcinomas.

Publications

Somatic mutations favorable to patient survival are predominant in ovarian carcinomas.

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