Abstract
Genome-wide studies of patients carrying pathogenic variants (mutations) in BRCA1 or BRCA2 have reported strong associations between single-nucleotide polymorphisms (SNPs) and cancer risk. To conduct the first genome-wide association analysis of copy-number variants (CNVs) with breast or ovarian cancer risk in a cohort of 2500 BRCA1 pathogenic variant carriers, CNV discovery was performed using multiple calling algorithms and Illumina 610k SNP array data from a previously published genome-wide association study. Our analysis, which focused on functionally disruptive genomic deletions overlapping gene regions, identified a number of loci associated with risk of breast or ovarian cancer for BRCA1 pathogenic variant carriers. Despite only including putative deletions called by at least two or more algorithms, detection of selected CNVs by ancillary molecular technologies only confirmed 40% of predicted common (>1% allele frequency) variants. These include four loci that were associated (unadjusted P<0.05) with breast cancer (GTF2H2, ZNF385B, NAALADL2 and PSG5), and two loci associated with ovarian cancer (CYP2A7 and OR2A1). An interesting finding from this study was an association of a validated CNV deletion at the CYP2A7 locus (19q13.2) with decreased ovarian cancer risk (relative risk=0.50, P=0.007). Genomic analysis found this deletion coincides with a region displaying strong regulatory potential in ovarian tissue, but not in breast epithelial cells. This study highlighted the need to verify CNVs in vitro, but also provides evidence that experimentally validated CNVs (with plausible biological consequences) can modify risk of breast or ovarian cancer in BRCA1 pathogenic variant carriers.
Highlights
Carriers of BRCA1 pathogenic variants are at increased risk for developing breast cancer and/or ovarian cancer, but the precise level of these risks is uncertain
Genome-wide copy-number variant (CNV) analysis was performed on 2319 individuals with pathogenic BRCA1 pathogenic variants, including 1202 breast cancer cases (1117 non-breast cancer affected) and 357 ovarian cancer cases (1962 non-ovarian cancer affected), using published genotype data from Illumina 610K single-nucleotide polymorphisms (SNPs) arrays.[14]
Compared with SNPs, the contribution of CNVs to genetic variability and breast and/or ovarian cancer risk is relatively unknown. This is the first genome-wide CNV association study of BRCA1 pathogenic variant carriers to identify CNVs that are associated with breast and/ or ovarian cancer risk, and the first implementation of the retrospective likelihood to CNV data
Summary
Carriers of BRCA1 pathogenic variants are at increased risk for developing breast cancer and/or ovarian cancer, but the precise level of these risks is uncertain. CNVs have been shown to partially overlap or fully encompass genes or regulatory sequences resulting in a range of biological changes, such as altered gene expression.[8] Importantly, these inherited structural variants have a role in many complex diseases,[9] and comprise a proportion of the mutation spectrum for known cancer syndromes, such as hereditary breast–ovarian cancer syndrome, Lynch syndrome and Li–Fraumeni syndrome.[10] recent genome-wide CNV studies have reported associations between a common deletion polymorphism overlapping APOBEC3 and risk of both breast and ovarian cancer.[11,12,13] other common and rare CNVs may affect genes involved in cancer-related pathways. The contribution of germline CNVs to variable risk in individuals with deleterious BRCA1 pathogenic variants is unknown
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