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Walker LC , Marquart L , Pearson JF , Wiggins GA , O'Mara TA , Parsons MT , Barrowdale D , McGuffog L , Dennis J , Benitez J , Slavin TP , Radice P , Frost D , Godwin AK , Meindl A , Schmutzler RK , Isaacs C , Peshkin BN , Caldes T , Hogervorst FB , Lazaro C , Jakubowska A , Montagna M , Chen X , Offit K , Hulick PJ , Andrulis IL , Lindblom A , Nussbaum RL , Nathanson KL , Chenevix-Trench G , Antoniou AC , Couch FJ , Spurdle AB
Evaluation of copy-number variants as modifiers of breast and ovarian cancer risk for BRCA1 pathogenic variant carriers
Eur J Hum Genet. 2017 Apr;25(4) :432-438
PMID: 28145423 PMCID: PMC5386423
AbstractGenome-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.
Notes1476-5438 Walker, Logan C Marquart, Louise Pearson, John F Wiggins, George A R O'Mara, Tracy A Parsons, Michael T Bcfr Barrowdale, Daniel McGuffog, Lesley Dennis, Joe Benitez, Javier Slavin, Thomas P Radice, Paolo Frost, Debra Embrace Godwin, Andrew K Meindl, Alfons Schmutzler, Rita Katharina GEMO Study Collaborators Isaacs, Claudine Peshkin, Beth N Caldes, Trinidad Hogervorst, Frans Bl Hebon Lazaro, Conxi Jakubowska, Anna Montagna, Marco KConFab Investigators Chen, Xiaoqing Offit, Kenneth Hulick, Peter J Andrulis, Irene L Lindblom, Annika Nussbaum, Robert L Nathanson, Katherine L Orcid: 0000-0002-6740-0901 Chenevix-Trench, Georgia Antoniou, Antonis C Couch, Fergus J Spurdle, Amanda B R01 CA140323/CA/NCI NIH HHS/United States R01 CA176785/CA/NCI NIH HHS/United States RC4 CA153828/CA/NCI NIH HHS/United States UM1 CA164920/CA/NCI NIH HHS/United States P30 CA168524/CA/NCI NIH HHS/United States U01 CA116167/CA/NCI NIH HHS/United States R01 CA083855/CA/NCI NIH HHS/United States P30 CA051008/CA/NCI NIH HHS/United States R01 CA116167/CA/NCI NIH HHS/United States P50 CA116201/CA/NCI NIH HHS/United States U01 CA113916/CA/NCI NIH HHS/United States R01 CA102776/CA/NCI NIH HHS/United States R01 CA192393/CA/NCI NIH HHS/United States P30 CA006927/CA/NCI NIH HHS/United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Eur J Hum Genet. 2017 Apr;25(4):432-438. doi: 10.1038/ejhg.2016.203. Epub 2017 Feb 1.