Walker, Logan ORCID: 0000-0003-0018-3719, Marquart, Louise, Pearson, John, Wiggins, George, O'Mara, Tracy ORCID: 0000-0002-5436-3232, Parsons, Michael T., Barrowdale, Daniel ORCID: 0000-0003-1661-3939, McGuffog, Lesley, Dennis, Joe, Benitez, Javier, Slavin, Thomas P., Radice, Paolo ORCID: 0000-0001-6298-4111, Frost, Debra, Godwin, Andrew K., Meindl, Alfons, Schmutzler, Rita Katharina, Isaacs, Claudine, Peshkin, Beth N., Caldes, Trinidad, Hogervorst, Frans B. L., Lazaro, Conxi, Jakubowska, Anna ORCID: 0000-0002-5650-0501, Montagna, Marco, Chen, Xiaoqing, Offit, Kenneth, Hulick, Peter J., Andrulis, Irene L., Lindblom, Annika, Nussbaum, Robert L., Nathanson, Katherine L., Chenevix-Trench, Georgia ORCID: 0000-0002-1878-2587, Antoniou, Antonis C., Couch, Fergus J. and Spurdle, Amanda B. (2017). Evaluation of copy-number variants as modifiers of breast and ovarian cancer risk for BRCA1 pathogenic variant carriers. Eur. J. Hum. Genet., 25 (4). S. 432 - 439. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5438

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Walker, LoganUNSPECIFIEDorcid.org/0000-0003-0018-3719UNSPECIFIED
Marquart, LouiseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pearson, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wiggins, GeorgeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
O'Mara, TracyUNSPECIFIEDorcid.org/0000-0002-5436-3232UNSPECIFIED
Parsons, Michael T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barrowdale, DanielUNSPECIFIEDorcid.org/0000-0003-1661-3939UNSPECIFIED
McGuffog, LesleyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dennis, JoeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benitez, JavierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Slavin, Thomas P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Radice, PaoloUNSPECIFIEDorcid.org/0000-0001-6298-4111UNSPECIFIED
Frost, DebraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Godwin, Andrew K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meindl, AlfonsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmutzler, Rita KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Isaacs, ClaudineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peshkin, Beth N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caldes, TrinidadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hogervorst, Frans B. L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lazaro, ConxiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jakubowska, AnnaUNSPECIFIEDorcid.org/0000-0002-5650-0501UNSPECIFIED
Montagna, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, XiaoqingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Offit, KennethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hulick, Peter J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andrulis, Irene L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lindblom, AnnikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nussbaum, Robert L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nathanson, Katherine L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chenevix-Trench, GeorgiaUNSPECIFIEDorcid.org/0000-0002-1878-2587UNSPECIFIED
Antoniou, Antonis C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Couch, Fergus J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spurdle, Amanda B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-235065
DOI: 10.1038/ejhg.2016.203
Journal or Publication Title: Eur. J. Hum. Genet.
Volume: 25
Number: 4
Page Range: S. 432 - 439
Date: 2017
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1476-5438
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
APOBEC3 DELETION POLYMORPHISM; HIDDEN-MARKOV MODEL; MUTATION CARRIERS; EXPRESSION; SUSCEPTIBILITY; GALAXY; LOCUS; MAPMultiple languages
Biochemistry & Molecular Biology; Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/23506

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