Effects of germline and somatic events in candidate BRCA-like genes on breast-tumor signatures

Mutations inBRCA1andBRCA2cause 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 responses to platinum salt therapies and PARP inhibitors. Among other consequences of HR deficiency are characteristic somatic-mutation signatures and gene-expression patterns. The term "BRCA-like" (or "BRCAness") describes tumors that harbor an HR defect but have no detectable germline mutation inBRCA1orBRCA2. A better understanding of the genes and molecular events associated with tumors being BRCA-like could provide mechanistic insights and guide development of targeted treatments. Using data from The Cancer Genome Atlas (TCGA) for 1101 breast-cancer patients, we identified individuals with a germline mutation, somatic mutation, homozygous deletion, and/or hypermethylation event inBRCA1,BRCA2, and 59 other cancer-predisposition genes. Based on the assumption that BRCA-like events would have similar downstream effects on tumor biology asBRCA1/BRCA2germline mutations, we quantified these effects based on somatic-mutation signatures and gene-expression profiles. We reduced the dimensionality of the somatic-mutation signatures and expression data and used a statistical resampling approach to quantify similarities among patients who had aBRCA1/BRCA2germline mutation, another type of aberration inBRCA1orBRCA2, or any type of aberration in one of the other genes. Somatic-mutation signatures of tumors having a non-germline aberration inBRCA1/BRCA2(n = 80) were generally similar to each other and to tumors fromBRCA1/BRCA2germline carriers (n = 44). Additionally, somatic-mutation signatures of tumors with germline or somatic events inATR(n = 16) andBARD1(n = 8) showed high similarity to tumors fromBRCA1/BRCA2carriers. Other genes (CDKN2A,CTNNA1,PALB2,PALLD,PRSS1,SDHC) also showed high similarity but only for a small number of events or for a single event type. Tumors with germline mutations or hypermethylation ofBRCA1had relatively similar gene-expression profiles and overlapped considerably with the Basal-like subtype; but the transcriptional effects of the other events lacked consistency. Our findings confirm previously known relationships between molecular signatures and germline or somatic events inBRCA1/BRCA2. Our methodology represents an objective way to identify genes that have similar downstream effects on molecular signatures when mutated, deleted, or hypermethylated.