Rare Copy Number Variants Observed in Hereditary Breast Cancer Cases Disrupt Genes in Estrogen Signaling and TP53 Tumor Suppression Network

Abstract

Breast cancer is the most common cancer in women in developed countries, and the contribution of genetic susceptibility to breast cancer development has been well-recognized. However, a great proportion of these hereditary predisposing factors still remain unidentified. To examine the contribution of rare copy number variants (CNVs) in breast cancer predisposition, high-resolution genome-wide scans were performed on genomic DNA of 103 BRCA1, BRCA2, and PALB2 mutation negative familial breast cancer cases and 128 geographically matched healthy female controls; for replication an independent cohort of 75 similarly mutation negative young breast cancer patients was used. All observed rare variants were confirmed by independent methods. The studied breast cancer cases showed a consistent increase in the frequency of rare CNVs when compared to controls. Furthermore, the biological networks of the disrupted genes differed between the two groups. In familial cases the observed mutations disrupted genes, which were significantly overrepresented in cellular functions related to maintenance of genomic integrity, including DNA double-strand break repair (P = 0.0211). Biological network analysis in the two independent breast cancer cohorts showed that the disrupted genes were closely related to estrogen signaling and TP53 centered tumor suppressor network. These results suggest that rare CNVs represent an alternative source of genetic variation influencing hereditary risk for breast cancer. Although genetic susceptibility to breast cancer has been well-established, the majority of the predisposing factors still remain unidentified. Here, we have taken advantage of recent technical and methodological advances to examine the role of a new class of genomic variation, rare copy number variants (CNVs), in hereditary predisposition to breast cancer. By examining 103 BRCA1/2 and PALB2 mutation negative familial and 75 young breast cancer cases, together with 128 geographically matched healthy female controls, we show that the frequency of rare CNVs is increased in cases when compared to controls and that the genes disrupted in individuals of specifically the two case groups are closely related to estrogen signaling and TP53 centered tumor suppressor network. The variety of disrupted genes belonging to these networks underscores that diverse mechanisms are likely to be relevant to breast cancer pathogenesis. The current results warrant the investigation of rare CNVs as new susceptibility factors in other cancer types as well.