Evidence that 5p12 variant rs10941679 confers susceptibility to estrogen-receptor-positive breast cancer through FGF10 and MRPS30 regulation

Etiology (underlying causes) of breast cancer remain among the biggest mysteries in current cancer research. And, after this publication, breast cancer etiology remains as big a mystery as before.

Genome-wide association studies (GWAS) have revealed increased breast cancer risk associated with multiple genetic variants located at chromosomal 5p12. Authors report [see the attached report] the fine-mapping of this locus––using data from 104,660 subjects derived from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1-Mb region, authors found evidence for at least three independent signals: the strongest signal, consisting of a single SNP (rs10941679), was associated with risk of estrogen-receptor-positive (ER+) breast cancer (OR=1.15; 95% CI 1.13–1.18; P = 8.35e–30).

After adjustment for rs10941679, authors detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER–) breast cancer (lead SNP rs6864776: OR=1.10; 95% CI 1.05–1.14; Pconditional = 1.44e–12), and a single signal 3: SNP (rs200229088) (OR=1.12; 95% CI 1.09–1.15; Pconditional = 1.12e–05). Expression quantitative-trait locus (eQTL) analysis in normal breast tissues and breast tumors revealed the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30.

Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with fibroblast growth factor-10 (FGF10) and mitochondrial ribosome protein-S30 (MRPS30) promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to fibroblast-growth-factor receptor-2 (FGFR2) and is over-expressed in ~10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis (programmed cell death). These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.

Am J Hum Genet 6 Oct 2o16; 99: 903–911

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