title: A genomic instability score in discriminating nonequivalent outcomes of BRCA1/2 mutations and in predicting outcomes of ovarian cancer treated with platinum-based chemotherapy.
abstract: Detecting mutation in BRCA1/2 is a generally accepted strategy for screening ovarian cancers that have impaired homologous recombination (HR) ability and improved sensitivity to PARP inhibitor. However, a substantial subset of BRCA-mutant ovarian cancer patients shows less impaired or unimpaired HR ability, resulting in nonequivalent outcome after ovarian cancer development. We hypothesize that genomic instability provides a lifetime record of DNA repair deficiency and predicts ovarian cancer outcome. Based on the multi-dimensional TCGA ovarian cancer data, we developed a biological rationale-driven genomic instability score integrating somatic mutation and copy number change in a tumor genome. The score successfully divided BRCA-mutant ovarian tumors into cases of significantly improved outcome and cases of unimproved outcome. The score was also capable of discriminating HR-deficiency indicated by BRCA1 epigenetically silencing, EMSY amplification and homozygous deletion of core HR genes. We further found that the score was positively correlated with the complete response rate of chemotherapy and the rate of platinum-sensitivity, and predicted improved outcome of ovarian cancer, regardless of BRCA-mutation status. The score may have important value in outcome prediction and clinical trial design.
authors.affiliation: College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, P.R. China.
authors.forename: Shaojun
authors.initials: S
authors.lastname: Zhang
authors.affiliation: College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, P.R. China; Department of Gynecology and Obstetrics, The Forth Affiliated Hospital of Harbin Medical University, Department of Gynecology and Obstetrics, Harbin 150081, P.R. China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, P.R. China.
authors.forename: Dapeng
authors.initials: D
authors.lastname: Hao
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D042822:Genomic Instability / Q000235:genetics*; D059765:Homologous Recombination / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D010984:Platinum / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011379:Prognosis; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D010984:Platinum