Comparison of 6q25 Breast Cancer Hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC)

Abstract

The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER−) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26–1.48), p = 7.6×10−14 in Asians and 1.09 (95% CI 1.07–1.11), p = 6.8×10−18 in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19–1.41), p = 1.2×10−9 in Asians and 1.12 (95% CI 1.08–1.17), p = 3.8×10−9 in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER− than ER+ tumours in Europeans [OR (ER−) = 1.20 (95% CI 1.15–1.25), p = 1.8×10−17 versus OR (ER+) = 1.07 (95% CI 1.04–1.1), p = 1.3×10−7, pheterogeneity = 5.1×10−6]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER− tumours.

Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer

“…SNPs associated with multiple phenotypes have been mapped to the ESR1 locus, notably breast cancer (Hein et al 2012; Turnbull et al 2010; Zheng et al 2009), which shares many risk factors with endometrial cancer, and age-of-menarche (Perry et al 2014) and bone mineral density (Estrada et al 2012), which are both associated with estrogen exposure. However, none of the SNPs reported by these studies are correlated with any of the variants found to be associated with endometrial cancer risk (r 2 < 0.2).…”

“…However, comprehensive candidate gene and genome-wide association studies of breast cancer, which shares many risk factors with endometrial cancer, have identified cancer-associated risk variants at the ESR1 locus (Dunning, et al 2009; Hein, et al 2012; Turnbull, et al 2010; Zheng, et al 2009). These findings indicate a need for similar large-scale and comprehensive genetic analysis of endometrial cancer to elucidate the role of ESR1 variants in the risk of endometrial cancer.…”

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.…”

Association of low-penetrance alleles with male breast cancer risk and clinicopathological characteristics: results from a multicenter study in Italy

“…At present, there are no data on possible correlations between clinicopathological characteristics and common low-penetrance BC susceptibility alleles in MBC. On the other hand, in FBC, there is increasing evidence that associations between common variants and BC risk could vary by clinically important tumor characteristics, mainly by ER expression [25][26][27][28][29][30][31]. We found that ESR1 was significantly associated with the risk of ER-BCs in males.…”

“…and ER-disease [25,27]. On the other hand, variants in ESR1 and 19p13 show evidence of an association primarily with ER-BCs [20,[29][30][31]. At present, there are no data on possible correlations between clinicopathological characteristics and common low-penetrance BC susceptibility alleles in MBC.…”