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.

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

“…Detailed functional studies will be required to define the underlying biology of SNP-regulatory interactions to identify the causal SNP(s) at each locus, and to confirm which candidate susceptibility genes represent the targets of these risk SNPs. Evolving technologies, in particular CRISPR-Cas9 genome editing, now enable precision modification of risk SNPs to create isogenic models of different alleles 35 , enabling the effects of each allele on disease pathogenesis to be studied, for example at 19p13 36 , 8q24 14 , 17q12 12 and 5p15 13 . Finally, given that several previously identified EOC susceptibility alleles are associated with risk of other cancers 17 , and that there are similarities in molecular phenotype and/or shared tissue of origin between endometrial cancer, endometriosis and ENOC and CCOC 37 as well as basal-like breast cancer 38 , we anticipate that the loci reported here may be also associated with risk of other cancer-related traits.…”

Modifiers of breast and ovarian cancer risks for BRCA1 and BRCA2 mutation carriers

“…Genotypes at many millions of common variants across the genome can be genotyped or imputed with high accuracy using largescale genotyping arrays, using reference panels from the 1000 Genomes Project (Auton et al 2015). This approach has been applied with great success in cancer epidemiology in the general population, with GWAS having identified more than 100 common susceptibility variants for breast cancer , Hunter et al 2007, Stacey et al 2007, Ahmed et al 2009, Thomas et al 2009, Antoniou et al 2010b, Turnbull et al 2010, Cai et al 2011, Fletcher et al 2011, Ghoussaini et al 2012, Hein et al 2012, Long et al 2012, Siddiq et al 2012, Bojesen et al 2013, French et al 2013, Garcia-Closas et al 2013, Gaudet et al 2013, Meyer et al 2013, Cai et al 2014, Milne et al 2014a, Orr et al 2015, Couch et al 2016, Dunning et al 2016, Lawrenson et al 2016, Zheng et al 2009) and 22 for ovarian cancer (Song et al 2009, Bolton et al 2010, Goode et al 2010, Bojesen et al 2013, Permuth-Wey et al 2013, Pharoah et al 2013, Kuchenbaecker et al 2015.…”

“…In this context, within CIMBA, four approaches have been applied to identify loci associated with breast and ovarian cancer for mutation carriers: (i) GWAS for breast and ovarian cancer specifically performed in samples of BRCA1 and BRCA2 mutation carriers (Antoniou et al 2010b, Gaudet et al 2013; (ii) association 23:10 studies to assess common breast and ovarian cancer susceptibility alleles identified in the general population as potential modifiers of risk for mutation carriers (Antoniou et al 2008b, Kuchenbaecker et al 2014; (iii) meta-analyses of GWAS performed in BRCA1 and BRCA2 mutation carriers with GWAS of related phenotypes in the general population (for example, combining studies of breast cancer risk for BRCA1 mutation carriers with those of oestrogen receptor-negative breast cancer in general population or studies of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers with GWAS of serous ovarian cancer in the general population) (Kuchenbaecker et al 2015, Couch et al 2016; and iv) finescale mapping of risk-modifying loci identified through GWAS approaches to fully characterise the associations with all genetic variants at these loci (Bojesen et al 2013, Dunning et al 2016, Lawrenson et al 2016.…”

“…Fine-mapping studies, in which a much denser selection of SNPs in susceptibility loci is genotyped and analysed using multivariable (conditional) 23:10 models, can highlight potentially causal variants, although extensive laboratory work is often required to demonstrate their function. These experiments are not feasible for all loci, and those that are, are often laborious and sometimes equivocal in identifying a single causal variant or even a single target gene (Dunning et al 2016, Lawrenson et al 2016). These fine-mapping studies often identify additional independent associations.…”

Characterizing Genetic Susceptibility to Breast Cancer in Women of African Ancestry

“…One additional variant, rs11571833 at chromosome 13q13, was not genotyped and could not be imputed in all 3 studies; this variant had a minor allele frequency of 0.006 in the 1000 Genomes AFR population. These 74 risk variants include stronger markers than the index SNP found in GWAS as well as independent signals discovered through subsequent fine-mapping studies (Supplemental Table S1) (1, 3, 4, 8, 10, 11). …”