Abstract 1337: The UGT1A6_19_GG genotype is associated with increased breast cancer risk based on a two-stage study.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Over 20 breast cancer susceptibility loci have been identified mainly by genome-wide association studies (GWAS). These include Fibroblast Growth Factor Receptor (FGFR2) and loci close to the cell cycle regulator Cyclin D1 (CCND1) at 11q13. Phase I and II enzymes are anticipated to also contribute to breast cancer risk due to their roles in the inactivation, detoxification and elimination of endogenous and exogenous carcinogenic compounds. However, a GWAS approach is inappropriate for many genes due to their high degree of sequence homologies. For the UDP glucuronosyltransferase 1 family, polypeptide A6 (UGT1A6), a key player in Phase II steroid metabolism, we pursued a candidate approach using a specific assay design for gene amplification. We focused on the UGT1A6\_19\_T>G polymorphism (rs6759892) because this variant has been suggested to decrease enzyme activity. Moreover, our prior efforts showed an association between the UGT1A6\_19\_GG genotype and increased breast cancer risk (OR 1.17; 95% CI: 1.03-1.34; p = 0.014) in two population-based breast cancer case-control studies from Germany (3,139 cases and 5,466 controls) (MARIE-GENICA, 2010, Breast Cancer Res Treat 119:463-74). To validate these findings we extended the analysis to four independent study collections from Finland (KBCP, OBCS), Germany (BBCC) and Sweden (SASBAC) comprising 3,635 cases and 2,648 controls. Moreover, we performed a pooled analysis of all study subjects (7,418 cases and 8,720 controls) all being of European descent. UGT1A6\_19\_T>G genotyping was done by Matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) and statistical analysis by logistic regression adjusted for age and study using SPSS. Power calculation was done with nQuery Advisor ® which showed that the pooled study had an 80% power to detect a minimum OR of 1.06 (α = 0.05, two-sided test). The analysis of the BBCC, KBCP, OBCS and SASBAC collections confirmed our previous findings showing an increased overall breast cancer risk among women with the UGT1A6\_19\_GG genotype (OR 1.13; 95% CI: 1.05-1.22; p = 0.001). The pooled study showed a similar effect (OR 1.09; 95% CI: 1.04-1.14; p = 0.0004). We conclude based on the significant association between the UGT1A6\_19\_GG variant and breast cancer that a decreased conjugation activity of UGT1A6 might elevate the exposure to carcinogenic compounds thereby increasing the risk of breast cancer. Citation Format: Ofure M. Obazee, Christina Justenhoven, Stefan Winter, Sylvia Rabstein, Anne Lotz, Volker Harth, Beate Pesch, Thomas Bruning, Christian Baisch, Jaana M. Hartikainen, Arto Mannermaa, Robert Winqvist, Peter Fasching, Per Hall, Jenny Chang-Claude, Ute Hamann, Yon-Dschun Ko, Hiltrud Brauch. The UGT1A6\_19\_GG genotype is associated with increased breast cancer risk based on a two-stage study. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1337. doi:10.1158/1538-7445.AM2013-1337