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Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170

Dunning, A.M., Michailidou, K., Kuchenbaecker, K.B., et al.

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER+ or ER) and human ERBB2 (HER2+ or HER2) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.

SNPs at 6q25.1 have been reported to be associated with breast cancer susceptibility in genome-wide association studies (GWAS) in women of Chinese and European ancestry. Subsequent analyses have demonstrated that SNPs in the same region are associated with breast cancer risk for BRCA1 mutation carriers and mammographic density, a strong breast cancer risk factor. Thus far, however, attempts to identify the candidate causal variant(s) underlying the associations have been inconclusive. Here we report fine-scale mapping and comprehensive analysis of the genotype-phenotype associations in this region, using dense genotyping and imputed data from the custom-designed iCOGS array, in 118,816 subjects from three consortia: the Breast Cancer Association Consortium (BCAC), the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) and the Markers of Density Consortium (MODE). We additionally demonstrate, through functional analyses, the likely modes of action of the strongest candidate causal variants.

Citation

Dunning, A.M., Michailidou, K., Kuchenbaecker, K.B., et al. "Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170" Nature Genetics (2016): 374–86