Multi-omics analysis reveals the BRCA1 mutation and mismatch repair gene signatures associated with survival, protein expression, and copy number alterations in prostate cancer.

Abstract

BackgroundRecent genomic analysis reveals that DNA repair gene mutations can be detected in 15–30% of patients in metastatic castration resistant prostate cancer depending on the population and clinical setting when comparing to a very small fraction in those with indolent localized diseases. The discovery and characterization of function associated with DNA repair gene mutations in prostate cancer patients may increase therapeutic options and lead to improved clinical outcomes.MethodsTo understand the role of DNA repair genes associated with other genomic alteration and signaling pathway, we applied an integrative analysis of multi-omics to The Cancer Genome Atlas (TCGA) prostate cancer dataset which contains 498 patients. We concurrently analyzed gene expression profiles, reverse phase protein lysate microarray (RPPA) data, and copy number alterations to examine the potential genomic mechanisms.ResultsWe identified the signature of “chromosome condensation”, “BRCA1 mutation”, and “mismatch repair” were associated with disease-free survival in prostate cancer. Through the concurrent analysis of gene expression profiles, reverse RPPA data, and copy number alterations, we found the three signatures are associated with cell cycle and DNA repair pathway and also most events of copy number gains.ConclusionsThis study presents a unique extension from DNA mutations to expressional functions, proteomic activities, and copy numbers of DNA repair genes in prostate cancer. Our findings revealed crucial prognostic markers and candidates for further biological and clinical investigations.