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Nature Research, Nature Communications, 1(7), 2016

DOI: 10.1038/ncomms12675

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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

Journal article published in 2016 by Le E. van der Kolk, Cc C. van der Pol, Anna deFazio, Antoine de Pauw, Fe E. van Leeuwen, Jl L. de Lange, Chm H. M. van Deurzen, Cj J. van Asperen, Tctef C. T. E. F. van Cronenburg, Tam A. M. van Os, Gh H. de Bock, Miguel de la Hoya, Amw M. W. van den Ouweland, Hc C. van Doorn, Ej J. van Rensburg and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P¼9.2 10 20), ER-negative BC (P¼1.1 10 13), BRCA1-associated BC (P¼7.7 10 16) and triple negative BC (P-diff¼2 10 5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P¼2 10 3) and ABHD8 (Po2 10 3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 30-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk. ; The COGS project is funded through a European Commission’s Seventh Framework Programme grant (agreement number 223175—HEALTH-F2-2009- 223175). BCAC is funded by Cancer Research UK [C1287/A10118, C1287/A12014] and by the European Community´s Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). The CIMBA data management and analytical work is funded by Cancer Research UK (C12292/A11174, C12292/A20861). Funding for the iCOGS infrastructure came from: the European Community’s Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME-ON Post-GWAS Initiative (U19-CA148112). This study made use of data generated by the Wellcome Trust Case Control consortium. Funding for the project was provided by the Wellcome Trust under award 076113. The results published here are in part based on data generated by The Cancer Genome Atlas Project established by the National Cancer Institute and National Human Genome Research Institute. ; http://www.nature.com/naturecommunications ; am2016 ; Genetics