Markers of BRCAness in breast cancer

Abstract

Abstract Background Mutations in BRCA1 and BRCA2 cause deficiencies in homologous recombination repair (HR), resulting in repair of DNA double-strand breaks by the alternative non-homologous end-joining pathway, which is more error prone. HR deficiency of breast tumors is important because it is associated with better response to platinum salt therapies and to PARP inhibitors. Among other consequences of HR deficiency are characteristic somatic-mutation signatures and transcriptomic patterns. The term “BRCAness” describes tumors that harbor an HR defect but have no detectable germline mutation in BRCA1 or BRCA2. A better understanding of the genes and molecular aberrations associated with BRCAness could provide mechanistic insights and guide development of targeted treatments. Methods Using The Cancer Genome Atlas (TCGA) genomic data from breast cancers in 1101 patients, we identified tumors with BRCAness based on somatic mutations, homozygous deletions, and hypermethylation of BRCA1 and BRCA2. We then evaluated germline mutations, somatic mutations, homozygous deletions, and hypermethylation of 24 other breast-cancer predisposition genes. Using somatic-mutation signatures, we compared these groups against tumors from 44 TCGA patients with germline mutations in BRCA1 or BRCA2. We also compared gene-expression profiles of tumors with BRCAness versus tumors from BRCA1 and BRCA2 mutation carriers. A statistical resampling approach enabled objective quantification of similarities among tumors, and dimensionality reduction enabled graphical characterizations of these relationships. Results Somatic-mutation signatures of tumors having a BRCA1/BRCA2 somatic mutation, homozygous deletion, or hypermethylation (n = 64) were markedly similar to each other and to tumors from BRCA1/BRCA2 germline carriers (n = 44). Furthermore, somatic-mutation signatures of tumors with germline or somatic events in BARD1 or RAD51C showed high similarity to tumors from BRCA1/BRCA2 carriers. These findings coincide with the roles of these genes in HR and support their candidacy as genes critical to BRCAness. As expected, tumors with either germline or somatic events in BRCA1 were enriched for basal gene-expression features. Conclusions Somatic-mutation signatures reflect the effects of HR deficiencies in breast tumors. Somatic-mutation signatures have potential as biomarkers of treatment response and to decipher the mechanisms of HR deficiency.