Association of an ancestry-specific variant near the <i>ESR1</i> gene with cancer risk and breast density in women of self-reported Hispanic ancestry.

10513 Background: A single-nucleotide polymorphism (SNP), rs140068132, located in the 6q25 region near the ESR1 gene, is common in self-reported Hispanic women but rare or absent in other populations. Previous studies have shown that rs140068132 is associated with a significantly reduced risk of breast cancer (BC) and may be particularly protective against triple-negative BC (TNBC). Further research suggests that rs140068132 may be linked to lower breast density. However, existing studies have been small, yielding imprecise estimates, and potential associations with cancers beyond BC remain unknown. Methods: We examined associations of rs140068132 with BC, TNBC, ovarian cancer (OC), endometrial cancer (EC), and BI-RADS breast density in a consecutive cohort of self-reported Hispanic women referred for hereditary cancer testing with a multigene panel. Cancer associations of rs140068132 were estimated as odds ratios (ORs), with 95% confidence intervals (CIs), from multivariable logistic regression models adjusted for personal/family cancer history, genetic ancestry, and age. We used Fisher’s Exact Test to determine whether homozygous rs140068132 carriers had lower BI-RADS breast density than heterozygous or non-carriers. P-values are reported as two-sided. Results: Among 55,463 Hispanic women, 9,304 (16.8%) were affected by BC, 998 (1.8%) by TNBC, 1,520 (2.7%) by OC, and 1,616 (2.9%) by EC. 2,053 women were unaffected and had breast density assessment. 9,665 (17.4%) women were heterozygous for rs140068132, and 629 (1.1%) were homozygous. Consistent with previous studies, we found a highly significant protective effect per allele of rs140068132 for overall BC (OR 0.64; 95% CI 0.60-0.69; p = 6.1 x 10 -37 ) and TNBC (OR 0.53; 95% CI 0.44-0.64; p = 7.4 x 10 -11 ). This finding translates to an overall BC risk reduction of 1.6-fold for heterozygous and 2.4-fold for homozygous carriers compared to non-carriers. TNBC risk was reduced by 1.9-fold for heterozygous and 3.6-fold for homozygous carriers compared to non-carriers. Homozygous rs140068132 carriers were more than 3 times less likely to have high (heterogeneously or extremely dense) breast density compared to heterozygous or non-carriers (OR 3.30; 95% CI 1.22-10.35; p = 0.0095). rs140068132 was not associated with risk of OC (OR 0.98; 95% CI 0.86-1.11; p = 0.77) or EC (OR 1.08; 95% CI 0.96-1.21; p = 0.23). Conclusions: We present findings from the largest study to date on cancer risks associated with rs140068132. Our research indicates that rs140068132 does not substantially affect the risk of OC or EC. We confirmed previous reports of significantly reduced risk of BC, particularly TNBC, among carriers of rs140068132, and we provided precise estimates of the ORs per allele. These findings have important implications for genetic risk assessment and may guide personalized BC prevention and treatment strategies.