2026-07-21T11:53:58Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/74332024-11-29T15:16:23Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Walker, Logan C author Marquart, Louise author Pearson, John F author Wiggins, George A R author O'Mara, Tracy A author Parsons, Michael T author Barrowdale, Daniel author McGuffog, Lesley author Dennis, Joe author Benitez, Javier author Slavin, Thomas P author Radice, Paolo author Frost, Debra author Godwin, Andrew K author Meindl, Alfons author Schmutzler, Rita Katharina author Isaacs, Claudine author Peshkin, Beth N author Caldes, Trinidad author Hogervorst, Frans Bl author Lazaro, Conxi author Jakubowska, Anna author Montagna, Marco author Chen, Xiaoqing author Offit, Kenneth author Hulick, Peter J author Andrulis, Irene L author Lindblom, Annika author Nussbaum, Robert L author Nathanson, Katherine L author Chenevix-Trench, Georgia author Antoniou, Antonis C author Couch, Fergus J author Spurdle, Amanda B author 2017-04-25 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. Eur J Hum Genet. 2017;25(4):432-438 10.1038/ejhg.2016.203 1476-5438 1018-4813 European journal of human genetics : EJHG 28145423 http://hdl.handle.net/20.500.12105/7433 Evaluation of copy-number variants as modifiers of breast and ovarian cancer risk for BRCA1 pathogenic variant carriers