Evaluation of copy-number variants as modifiers of breast and ovarian cancer risk for BRCA1 pathogenic variant carriers Journal Article

Authors: Walker, L. C.; Marquart, L.; Pearson, J. F.; Wiggins, G. A. R.; O'Mara, T. A.; Parsons, M. T.; Barrowdale, D.; McGuffog, L.; Dennis, J.; Benitez, J.; Slavin, T. P.; Radice, P.; Frost, D.; Godwin, A. K.; Meindl, A.; Schmutzler, R. K.; Isaacs, C.; Peshkin, B. N.; Caldes, T.; Hogervorst, F. B. L.; Lazaro, C.; Jakubowska, A.; Montagna, M.; Chen, X.; Offit, K.; Hulick, P. J.; Andrulis, I. L.; Lindblom, A.; Nussbaum, R. L.; Nathanson, K. L.; Chenevix-Trench, G.; Antoniou, A. C.; Couch, F. J.; Spurdle, A. B.
Article Title: Evaluation of copy-number variants as modifiers of breast and ovarian cancer risk for BRCA1 pathogenic variant carriers
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 copynumber 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.
Keywords: genes; genome; expression; susceptibility; mutation carriers; disease; hidden-markov model; snp genotyping data; apobec3 deletion polymorphism; galaxy
Journal Title: European Journal of Human Genetics
Volume: 25
Issue: 4
ISSN: 1018-4813
Publisher: Nature Publishing Group  
Date Published: 2017-04-01
Start Page: 432
End Page: 438
Language: English
ACCESSION: WOS:000395996200010
DOI: 10.1038/ejhg.2016.203
PMCID: PMC5386423
PUBMED: 28145423
Notes: Article -- Correction issued, see DOI: 10.1038/s41431-018-0216-1 -- Source: Wos
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  1. Kenneth Offit
    538 Offit