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Novel Breast Cancer Susceptibility Locus at 9q31.2: Results of a Genome-Wide Association Study

  1. Author:
    Fletcher, O.
    Johnson, N.
    Orr, N.
    Hosking, F. J.
    Gibson, L. J.
    Walker, K.
    Zelenika, D.
    Gut, I.
    Heath, S.
    Palles, C.
    Coupl, B.
    Broderick, P.
    Schoemaker, M.
    Jones, M.
    Williamson, J.
    Chilcott-Burns, S.
    Tomczyk, K.
    Simpson, G.
    Jacobs, K. B.
    Chanock, S. J.
    Hunter, D. J.
    Tomlinson, I. P.
    Swerdlow, A.
    Ashworth, A.
    Ross, G.
    Silva, I. D.
    Lathrop, M.
    Houlston, R. S.
    Peto, J.

  2. Author Address

    [Peto, Julian] London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, Noncommunicable Dis Epidemiol Unit, London WC1E 7HT, England. [Fletcher, Olivia; Johnson, Nichola; Orr, Nick; Palles, Claire; Coupland, Ben; Williamson, Jill; Chilcott-Burns, Sarah; Tomczyk, Katarzyna; Simpson, Gemma; Ashworth, Alan] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Hosking, Fay J.; Broderick, Peter; Houlston, Richard S.] Inst Canc Res, Sect Canc Genet, Surrey, England. [Zelenika, Diana; Gut, Ivo; Heath, Simon; Lathrop, Mark] IG CEA, Ctr Natl Genotypage, Evry, France. [Schoemaker, Minouk; Jones, Michael; Swerdlow, Anthony] Inst Canc Res, Epidemiol Sect, Surrey, England. [Jacobs, Kevin B.] NCI, Core Genotyping Facil, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Jacobs, Kevin B.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Jacobs, Kevin B.] BioInformed LLC, Gaithersburg, MD USA. [Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Tomlinson, Ian P.] Wellcome Trust Ctr Human Genet, Oxford, England. [Ross, Gillian] Royal Marsden NHS Fdn Trust, London, England. [Lathrop, Mark] Fdn Jean Dausett CEPH, Paris, France. [Peto, Julian] Inst Canc Res, Canc Res UK Genet & Epidemiol Grp, Surrey, England.;Peto, J, London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, Noncommunicable Dis Epidemiol Unit, Keppel St, London WC1E 7HT, England.;julian.peto@lshtm.ac.uk
    1. Year: 2011
    2. Date: Mar
  2. Journal: Journal of the National Cancer Institute
    1. 103
    2. 5
    3. Pages: 425-435
  4. Type of Article: Article
  5. ISSN: 0027-8874
  1. Abstract:

    Background Genome-wide association studies have identified several common genetic variants associated with breast cancer risk. It is likely, however, that a substantial proportion of such loci have not yet been discovered. Methods We compared 296 114 tagging single-nucleotide polymorphisms in 1694 breast cancer case subjects (92% with two primary cancers or at least two affected first-degree relatives) and 2365 control subjects, with validation in three independent series totaling 11 880 case subjects and 12 487 control subjects. Odds ratios (ORs) and associated 95% confidence intervals (CIs) in each stage and all stages combined were calculated using unconditional logistic regression. Heterogeneity was evaluated with Cochran Q and I-2 statistics. All statistical tests were two-sided. Results We identified a novel risk locus for breast cancer at 9q31.2 (rs865686: OR = 0.89, 95% CI = 0.85 to 0.92, P = 1.75 x 10(-10)). This single-nucleotide polymorphism maps to a gene desert, the nearest genes being Kruppel-like factor 4 (KLF4, 636 kb centromeric), RAD23 homolog B (RAD23B, 794 kb centromeric), and actin-like 7A (ACTL7A, 736 kb telomeric). We also identified two variants (rs3734805 and rs9383938) mapping to 6q25.1 estrogen receptor 1 (ESR1), which were associated with breast cancer in subjects of northern European ancestry (rs3734805: OR = 1.19, 95% CI = 1.11 to 1.27, P = 1.35 x 10(-7); rs9383938: OR = 1.18, 95% CI = 1.11 to 1.26, P = 1.41 x 10(-7)). A variant mapping to 10q26.13, approximately 300 kb telomeric to the established risk locus within the second intron of FGFR2, was also associated with breast cancer risk, although not at genome-wide statistical significance (rs10510102: OR = 1.12, 95% CI = 1.07 to 1.17, P = 1.58 x 10(-6)). Conclusions These findings provide further evidence on the role of genetic variation in the etiology of breast cancer. Fine mapping will be needed to identify causal variants and to determine their functional effects.

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  2. DOI: 10.1093/jnci/djq563
  3. View record in Web of Science®
  4. WOS: 000288020800011

Library Notes

  1. Fiscal Year: FY2010-2011
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