Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
Loading...
Date
Authors
Lawrenson, Kate
Kar, Siddhartha
McCue, Karen
Kuchenbaeker, Karoline
Michailidou, Kyriaki
Tyrer, Jonathan
Beesley, Jonathan
Ramus, Susan J.
Li, Qiyuan
Delgado, Melissa K.
Journal Title
Journal ISSN
Volume Title
Publisher
Nature Publishing Group
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.
Description
Keywords
Locus, Risk, Breast cancer (BC), Ovarian cancer (OC)
Sustainable Development Goals
Citation
Lawrenson, K. et al. Functional mechanisms underlying
pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus.
Nature Communications. 7:12675 doi: 10.1038/ncomms12675 (2016).