Abstract LB-413: A multi-stage association study in breast cancer identifies a protective allele at NCOA7

Estrogen metabolism and growth factor signaling pathway genes play a potential role in breast cancer predisposition. We evaluated pathway genes in a nested case-control investigation of women within the Nashville Breast Cohort, using germline DNA obtained from archival benign breast biopsies (formalin-fixed paraffin embedded). We applied methods enabling large-scale candidate gene investigation in the archival DNA (2 to 6 decades old). The study included 447 women who progressed to breast cancer (cases), and 838 women who did not (controls, matched on age and year of biopsy to cases in a ∼ 2:1 ratio). Single allele- and haplotype-based tests of association were explored among 115 tagged pathway genes, and results were compared to those of the CGEMS GWAS (1,145 cases, 1,142 controls). Findings across the two study populations were concordant in 8 genes. Further replication of results was sought in the Collaborative Breast Cancer Study (1,552 cases, 1,185 controls). FGFR2 and NCOA7 associations were concordant across all three studies. FGFR2 carries known susceptibility variants confirmed in prior GWAS, whereas the association at NCOA7 on 6q22.32 is novel. NCOA7 encodes a nuclear receptor co-activator that directly interacts with estrogen receptor to modulate its activity. A haplotype of NCOA7 had a significant inverse association with breast cancer in each of the three studies (odds ratios of 0.67, 0.77, and 0.78 (respectively) for haplotype carriers relative to non-carriers), with a combined odds ratio of 0.77 (95% CI 0.65-0.89), P = 5.1 × 10-4. These observations provide credible evidence that this NCOA7 variant has a protective effect on breast cancer risk. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-413.