TY - JOUR
T1 - Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
AU - KConFab Investigators
AU - The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON)
AU - EMBRACE
AU - GEMO Study Collaborators
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 - Choi, Ji Yeob
AU - Daly, Mary
N1 - Publisher Copyright:
© 2016 The Author(s).
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.
KW - Alleles
KW - Asian People/genetics
KW - Black People/genetics
KW - Breast Neoplasms/genetics
KW - Chromosomes, Human, Pair 19/genetics
KW - Female
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Genotype
KW - Humans
KW - Ovarian Neoplasms/genetics
KW - Polymorphism, Single Nucleotide
KW - RNA, Messenger/genetics
UR - http://www.scopus.com/inward/record.url?scp=84987880304&partnerID=8YFLogxK
U2 - 10.1038/ncomms12675
DO - 10.1038/ncomms12675
M3 - Article
C2 - 27601076
AN - SCOPUS:84987880304
SN - 2041-1723
VL - 7
SP - 12675
JO - Nature Communications
JF - Nature Communications
M1 - 12675
ER -
