TY - JOUR
T1 - Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
AU - GEMO Study Collaborators
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 - Evans, D Gareth
AU - Lophatananon, Artitaya
AU - Muir, Kenneth
AU - Shen, Chen-Yang
AU - Zheng, Wei
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.
U2 - 10.1038/ncomms12675
DO - 10.1038/ncomms12675
M3 - Article
C2 - 27601076
SN - 2041-1723
VL - 7
SP - 12675
JO - Nature Communications
JF - Nature Communications
ER -
