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.
Highlights
Breast cancer is the most common malignancy affecting women
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 copy number variants (CNVs) is increased in cases when compared to controls and that the genes disrupted in individuals of the two case groups are closely related to estrogen signaling and TP53 centered tumor suppressor network
Rare variants were defined as those that did not overlap over 60% with the common CNVs in Toronto Database of Genomic Variants, and all CNVs fulfilling the rare variant criteria were confirmed by independent method
Summary
Breast cancer is the most common malignancy affecting women. It is a complex disease with a well-established genetic component [1]; most of the familial and young breast cancer cases still remain unexplained by inherited mutations in the known susceptibility genes [2]. Multiple genome-wide association studies (GWAS) have identified several breast cancer associated single nucleotide polymorphisms (SNPs), but these have only modest effect sizes and explain much less of the heritability than originally anticipated [3]. With the exception of some specific founder mutations, these rare variants are individually infrequent, and even specific to single cases or families. Rare genomic microduplications and microdeletions, known as structural variants or copy number variants (CNVs), could represent an alternative class of genetic variation responsible for increased cancer risk
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