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

kConFab; The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON); EMBRACE; GEMO Study Collaboratorsz; Australian Ovarian Cancer Study Groupz

doi:10.1038/ncomms12675

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

kConFab
, The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON)
, EMBRACE
, GEMO Study Collaboratorsz
, Australian Ovarian Cancer Study Groupz

Department of Epidemiology and Environmental Health

University at Buffalo

University of Southern California
Cedars-Sinai Medical Center
University of Cambridge
Queensland Institute of Medical Research
Xiamen University
Dana-Farber Cancer Institute
Helsinki University Hospital
University of Toronto
University of California at Irvine
German Cancer Research Center
University of Texas MD Anderson Cancer Center
Karolinska Institutet
Rutgers - The State University of New Jersey, New Brunswick
IRCCS Istituto Europeo di Oncologia - Milano
Landspitali University Hospital
Friedrich-Alexander University Erlangen-Nürnberg
Spanish National Cancer Research Centre (CNIO)
Centro de Investigación en Red de Enfermedades Raras
Duke University
Memorial Sloan-Kettering Cancer Center
University of Bergen
Vanderbilt University
International Epidemiology Institute
Hannover Medical School
University of Southern Denmark
University of Copenhagen
University of Oslo
Robert Bosch Foundation
University of Tübingen
International Agency for Research on Cancer
Cancer Council Victoria
Institute Catala Oncologia
MOH Holdings Pte Ltd.
Heidelberg University
University of Helsinki
University of Utah
Hospital Clínico San Carlos de Madrid
Peter Maccallum Cancer Centre
Roswell Park Cancer Institute
University of Hamburg
Centre de Recherche du Centre Hospitalier de l'Université Laval (CRCHUL)

Research output: Contribution to journal › Article › peer-review

69 Scopus citations

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 (P=9.2 × 10^-20), ER-negative BC (P=1.1 × 10^-13), BRCA1-associated BC (P=7.7 × 10^-16) and triple negative BC (P-diff=2 × 10^-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10^-3) and ABHD8 (P<2 × 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 3′-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.

Original language	English
Article number	12675
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms12675
State	Published - Sep 7 2016

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@article{06bccfc8b5fb4d059f0f9b17f69068e0,

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

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 (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 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 3′-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.",

author = "kConFab and \{The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON)\} and EMBRACE and \{GEMO Study Collaboratorsz\} and \{Australian Ovarian Cancer Study Groupz\} and Kate Lawrenson and Siddhartha Kar and Karen McCue and Karoline Kuchenbaeker and Kyriaki Michailidou and Jonathan Tyrer and Jonathan Beesley and Ramus, \{Susan J.\} and Qiyuan Li and Delgado, \{Melissa K.\} and Lee, \{Janet M.\} and Kristiina Aittom{\"a}ki and Andrulis, \{Irene L.\} and Hoda Anton-Culver and Volker Arndt and Arun, \{Banu K.\} and Brita Arver and Bandera, \{Elisa V.\} and Monica Barile and Barkardottir, \{Rosa B.\} and Daniel Barrowdale and Beckmann, \{Matthias W.\} and Javier Benitez and Andrew Berchuck and Maria Bisogna and Line Bjorge and Carl Blomqvist and William Blot and Natalia Bogdanova and Anders Bojesen and Bojesen, \{Stig E.\} and Bolla, \{Manjeet K.\} and Bernardo Bonanni and B{\o}rresen-Dale, \{Anne Lise\} and Hiltrud Brauch and Paul Brennan and Hermann Brenner and Fiona Bruinsma and Joan Brunet and Buhari, \{Shaik Ahmad\} and Barbara Burwinkel and Ralf Butzow and Buys, \{Saundra S.\} and Qiuyin Cai and Trinidad Caldes and Ian Campbell and Rikki Canniotto and Jenny Chang-Claude and Jocelyne Chiquette and Moysich, \{Kirsten B.\}",

note = "Publisher Copyright: {\textcopyright} 2016 The Author(s).",

year = "2016",

month = sep,

day = "7",

doi = "10.1038/ncomms12675",

language = "English",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

TY - JOUR

T1 - Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

AU - kConFab

AU - The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON)

AU - EMBRACE

AU - GEMO Study Collaboratorsz

AU - Australian Ovarian Cancer Study Groupz

AU - Lawrenson, Kate

AU - Kar, Siddhartha

AU - McCue, Karen

AU - Kuchenbaeker, Karoline

AU - Michailidou, Kyriaki

AU - Tyrer, Jonathan

AU - Beesley, Jonathan

AU - Ramus, Susan J.

AU - Li, Qiyuan

AU - Delgado, Melissa K.

AU - Lee, Janet M.

AU - Aittomäki, Kristiina

AU - Andrulis, Irene L.

AU - Anton-Culver, Hoda

AU - Arndt, Volker

AU - Arun, Banu K.

AU - Arver, Brita

AU - Bandera, Elisa V.

AU - Barile, Monica

AU - Barkardottir, Rosa B.

AU - Barrowdale, Daniel

AU - Beckmann, Matthias W.

AU - Benitez, Javier

AU - Berchuck, Andrew

AU - Bisogna, Maria

AU - Bjorge, Line

AU - Blomqvist, Carl

AU - Blot, William

AU - Bogdanova, Natalia

AU - Bojesen, Anders

AU - Bojesen, Stig E.

AU - Bolla, Manjeet K.

AU - Bonanni, Bernardo

AU - Børresen-Dale, Anne Lise

AU - Brauch, Hiltrud

AU - Brennan, Paul

AU - Brenner, Hermann

AU - Bruinsma, Fiona

AU - Brunet, Joan

AU - Buhari, Shaik Ahmad

AU - Burwinkel, Barbara

AU - Butzow, Ralf

AU - Buys, Saundra S.

AU - Cai, Qiuyin

AU - Caldes, Trinidad

AU - Campbell, Ian

AU - Canniotto, Rikki

AU - Chang-Claude, Jenny

AU - Chiquette, Jocelyne

AU - Moysich, Kirsten B.

PY - 2016/9/7

Y1 - 2016/9/7

N2 - 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 (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 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 3′-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.

AB - 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 (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 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 3′-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.

UR - https://www.scopus.com/pages/publications/84987880304

U2 - 10.1038/ncomms12675

DO - 10.1038/ncomms12675

M3 - Article

C2 - 27601076

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 12675

ER -

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

Abstract

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