Abstract

The term "BRCAness" is used to describe breast-cancer patients who lack a germline mutation in BRCA1 or BRCA2, yet who are believed to express characteristics similar to patients who do have a germline mutation in BRCA1 or BRCA2. Although it is hypothesized that BRCAness is related to deficiency in the homologous recombination repair (HRR) pathways, relatively little is understood about what drives BRCAness or what criteria should be used to assign patients to this category. We hypothesized that patients whose tumor carries a genomic or epigenomic aberration in BRCA1 or BRCA2 should be classified under the BRCAness category and that these tumors would exhibit downstream effects (additional mutations or gene-expression changes) similar to patients with germline BRCA1/2 mutations. To better understand BRCAness, we examined similarities and differences in gene-expression profiles and somatic-mutation "signatures" among 1054 breast-cancer patients from The Cancer Genome Atlas. First, we categorized patients into three categories: those who carried a germline BRCA1/2 mutation, those whose tumor carried a genomic aberration or DNA hypermethylation in BRCA1/2 (the BRCAness group), and those who fell into neither of the first two groups. Upon evaluating the gene-expression data in context of the PAM50 subtypes, we did not observe significant similarity between the germline BRCA1/2 and BRCAness groups, but we did observe enrichment within the basal subtype, especially for BRCAness tumors with hypermethylation of BRCA1/2. However, the gene-expression profiles were fairly heterogeneous; for example, BRCA1 patients differed significantly from BRCA2 patients. In agreement with prior findings, certain mutational signatures—especially "Signature 3"—were enriched for patients with germline BRCA1/2 mutations as well as for BRCAness patients. Furthermore, we observed significant similarity between germline BRCA1/2 patients and patients with germline mutations in PALB2, RAD51B, and RAD51C, genes that are key parts of the HRR pathway and that interact with BRCA1/2. Our findings suggest that the BRCAness category does have biological and clinical relevance but that the criteria for including patients in this category should be carefully defined, potentially including BRCA1/2 hypermethylation and homozygous deletions as well as germline mutations in PALB2, RAD51B, and RAD51C.

Degree

College and Department

Life Sciences; Biology

Rights

http://lib.byu.edu/about/copyright/