Data from The 6q22.33 Locus and Breast Cancer Susceptibility

Abstract

<div>Abstract<p>Recently, we identified a novel breast cancer susceptibility locus at <i>6q22.33</i> following a genome-wide association study in the Ashkenazi Jewish genetic isolate. To replicate these findings, we did a case-control association analysis on <i>6q22.33</i> (rs2180341) in an additional 487 Ashkenazi Jewish breast cancer cases and in an independent non-Jewish, predominantly European American, population of 1,466 breast cancer cases and 1,467 controls. We confirmed the <i>6q22.33</i> association with breast cancer risk in the replication cohorts [per-allele odds ratio (OR), 1.18; 95% confidence interval (95% CI), 1.04-1.33; <i>P</i> = 0.0083], with the strongest effect in the aggregate meta-analysis of 3,039 breast cancer cases and 2,616 Ashkenazi Jewish and non-Jewish controls (per-allele OR, 1.24; 95% CI, 1.13-1.36; <i>P</i> = 3.85 × 10<sup>-7</sup>). We also showed that the association was slightly stronger with estrogen receptor–positive tumors (per-allele OR, 1.35; 95% CI, 1.20-1.51; <i>P</i> = 2.2 × 10<sup>-5</sup>) compared with estrogen receptor–negative tumors (per-allele OR, 1.19; 95% CI, 0.97-1.47; <i>P</i> = 0.1). Furthermore, this study provides a novel insight into the functional significance of <i>6q22.33</i> in breast cancer susceptibility. Due to the stronger association of <i>6q22.33</i> with estrogen receptor–positive breast cancer, we examined the effect of candidate genes on estrogen receptor response elements. Upon transfection of overexpressed <i>RNF146</i> in the MCF-7 breast cancer cell line, we observed diminished expression of an estrogen receptor response element reporter construct. This study confirms the association of <i>6q22.33</i> with breast cancer, with slightly stronger effect in estrogen receptor–positive tumors. Further functional studies of candidate genes are in progress, and a large replication analysis is being completed as part of an international consortium. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2468–75)</p></div>