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The 6q22.33 Locus and Breast Cancer Susceptibility

  1. Author:
    Kirchhoff, T.
    Chen, Z. Q.
    Gold, B.
    Pal, P.
    Gaudet, M. M.
    Kosarin, K.
    Levine, D. A.
    Gregersen, P.
    Spencer, S.
    Harlan, M.
    Robson, M.
    Klein, R. J.
    Hudis, C. A.
    Norton, L.
    Dean, M.
    Offit, K.

  2. Author Address

    Kirchhoff, Tomas, Pal, Prodipto, Kosarin, Kristi, Spencer, Sara, Harlan, Megan, Robson, Mark, Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Clin Genet Serv, Dept Med, New York, NY 10065 USA. [Gaudet, Mia M.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA. [Levine, Douglas A.] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA. [Klein, Robert J.] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA. [Hudis, Clifford A.; Norton, Larry] Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Breast Med Serv, New York, NY 10065 USA. [Gold, Bert, Dean, Michael] NCI Frederick, Expt Immunol Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD USA. [Gregersen, Peter] N Shore Long Isl Jewish Res Inst, Ctr Genom & Human Genet, Manhasset, NY USA. [Chen, Zhang-qun] SAIC Frederick, Basic Sci Program, Human Genet Sect, Frederick, MD USA.
    1. Year: 2009
  2. Journal: Cancer Epidemiology Biomarkers & Prevention
    1. 18
    2. 9
    3. Pages: 2468-2475
  4. Type of Article: Article
  1. Abstract:

    Recently, we identified a novel breast cancer susceptibility locus at 6q22.33 following a genome-wide association study in the Ashkenazi Jewish genetic isolate. To replicate these findings, we did a case-control association analysis on 6q22.33 (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 6q22.33 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, P = 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, P = 3.85 x 10(-7)). We also showed that the association was slightly stronger with estrogen receptorpositive tumors (per-allele OR, 1.35, 95% CI, 1.20-1.51, P = 2.2 x 10(-5)) compared with estrogen receptor-negative tumors (per-allele OR, 1.19, 95% CI, 0.97-1.47, P = 0.1). Furthermore, this study provides a novel insight into the functional significance of 6q22.33 in breast cancer susceptibility. Due to the stronger association of 6q22.33 with estrogen receptor-positive breast cancer, we examined the effect of candidate genes on estrogen receptor response elements. Upon transfection of overexpressed RNF146 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 6q22.33 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)

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  2. DOI: 10.1158/1055-9965.epi-09-0151
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