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

Logan C. Walker, Louise Marquart, John F. Pearson, George A.R. Wiggins, Tracy A. O'Mara, Michael T. Parsons, Daniel Barrowdale, Lesley McGuffog, Joe Dennis, Javier Benitez, Thomas P. Slavin, Paolo Radice, Debra Frost, Andrew K. Godwin, Alfons Meindl, Rita Katharina Schmutzler, Claudine Isaacs, Beth N. Peshkin, Trinidad Caldes, Frans B.L. HogervorstConxi Lazaro, Anna Jakubowska, Marco Montagna, Xiaoqing Chen, Kenneth Offit, Peter J. Hulick, Irene L. Andrulis, Annika Lindblom, Robert L. Nussbaum, Katherine L. Nathanson, Georgia Chenevix-Trench, Antonis C. Antoniou, Fergus J. Couch, Amanda B. Spurdle

Research output: Contribution to journalArticle

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)432-438
Number of pages7
JournalEuropean Journal of Human Genetics
Volume25
Issue number4
DOIs
StatePublished - Apr 1 2017

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    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., ... Spurdle, A. B. (2017). Evaluation of copy-number variants as modifiers of breast and ovarian cancer risk for BRCA1 pathogenic variant carriers. European Journal of Human Genetics, 25(4), 432-438. https://doi.org/10.1038/ejhg.2016.203