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Genome-wide association study provides evidence for a breast cancer risk locus at 6q22-33

  1. Author:
    Gold, B.
    Kirchhoff, T.
    Stefanov, S.
    Lautenberger, J.
    Viale, A.
    Garber, J.
    Friedman, E.
    Narod, S.
    Olshen, A. B.
    Gregersen, P.
    Kosarin, K.
    Olsh, A.
    Bergeron, J.
    Ellis, N. A.
    Klein, R. J.
    Clark, A. G.
    Norton, L.
    Dean, M.
    Boyd, J.

  2. Author Address

    Kirchhoff, Tomas, Kosarin, Kristi, Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Clin Genet Serv, Dept Med, New York, NY 10065 USA. [Gold, Bert, Stefanov, Stefan, Lautenberger, James, Olsh, Adam, Dean, Michael] NCI, Human Genet Sect, Lab Genom Divers, Frederick, MD 21702 USA. [Viale, Agnes] Mem Sloan Kettering Canc Ctr, Genome Core Lab, New York, NY 10065 USA. [Norton, Larry] Mem Sloan Kettering Canc Ctr, Breast Med Serv, New York, NY 10065 USA. [Olshen, Adam B.] Mem Sloan Kettering Canc Ctr, Dept Biostat & Epidemiol, New York, NY 10065 USA. [Klein, Robert J.] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA. [Garber, Judy] Dana Farber Canc Inst, Canc Risk & Prevent Program, Boston, MA 02115 USA. [Friedman, Eitan] Chaim Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, IL-52621 Tel Hashomer, Israel. [Friedman, Eitan] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. [Narod, Steven] Ctr Res Womens Hlth, Toronto, ON M5G 1N8, Canada. [Gregersen, Peter] N Shore Long Isl Jewish Res Inst, Ctr Genom & Human Genet, Manhasset, NY 11030 USA. [Bergeron, Julie] SAIC Frederick Inc, Human Genet Sect, Lab Genom Divers, Frederick, MD 21702 USA. [Ellis, Nathan A.] Univ Chicago, Dept Med, Div Gastroenterol, Chicago, IL 60637 USA. [Clark, Andrew G.] Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14853 USA. [Boyd, Jeff] Mem Hlth Univ Med Ctr, Anderson Canc Inst, Savannah, GA 31404 USA.
    1. Year: 2008
  2. Journal: Proceedings of the National Academy of Sciences of the United States of America
    1. 105
    2. 11
    3. Pages: 4340-4345
  4. Type of Article: Article
  1. Abstract:

    We performed a three-phase genome-wide association study (GWAS) using cases and controls from a genetically isolated population, Ashkenazi Jews (AJ), to identify loci associated with breast cancer risk. In the first phase, we compared allele frequencies of 150,080 SNPs in 249 high-risk, BRCA1/2 mutation-negative AJ familial cases and 299 cancer-free AJ controls using chi(2) and the Cochran-Armitage trend tests. In the second phase, we genotyped 343 SNPs from 123 regions most significantly associated from stage 1, including 4 SNPs from the FGFR2 region, in 950 consecutive AJ breast cancer cases and 979 age-matched AJ controls. We replicated major associations in a third independent set of 243 AJ cases and 187 controls. We obtained a significant allele P value of association with AJ breast cancer in the FGFR2 region (P = 1.5 x 10(-5), odds ratio (OR) 1.26, 95% confidence interval (CI) 1.13-1.40 at rs1078806 for all phases combined). In addition, we found a risk locus in a region of chromosome 6q22.33 (P = 2.9 x 10(-8), OR 1.41, 95% Cl 1.25-1.59 at rs2180341). Using several SNPs at each implicated locus, we were able to verify associations and impute haplotypes. The major haplotype at the 6q22.33 locus conferred protection from disease, whereas the minor haplotype conferred risk. Candidate genes in the 6q22.33 region include ECHDC1, which encodes a protein involved in mitochondrial fatty acid oxidation, and also RNF146, which encodes a ubiquitin protein ligase, both known pathways in breast cancer pathogenesis.

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External Sources

  1. PMID: 18326623

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