Novel breast cancer susceptibility locus at 9q31.2: results of a genome-wide association study

Olivia Fletcher, Nichola Johnson, Nick Orr, Fay J Hosking, Lorna J Gibson, Kate Walker-Springett, Diana Zelenika, Ivo Gut, Simon Heath, Claire Palles, Ben Coupland, Peter Broderick, Minouk Schoemaker, Michael Jones, Jill Williamson, Sarah Chilcott-Burns, Katarzyna Tomczyk, Gemma Simpson, Kevin B Jacobs, Stephen J. ChanockDavid J Hunter, Ian P Tomlinson, Anthony J Swerdlow, Alan Ashworth, Gillian Ross, Isabel Dos-Santos-Silva, Mark Lathrop, Richard S Houlston, Julian Peto

Research output: Contribution to journalArticlepeer-review

186 Citations (Scopus)


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 × 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 × 10(-7); rs9383938: OR = 1.18, 95% CI = 1.11 to 1.26, P = 1.41 × 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 × 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.

Original languageEnglish
Pages (from-to)425-35
Number of pages11
JournalJournal of the National Cancer Institute
Issue number5
Publication statusPublished - 02 Mar 2011


  • Actins
  • Adult
  • Aged
  • Breast Neoplasms
  • Case-Control Studies
  • Chromosomes, Human, Pair 10
  • Chromosomes, Human, Pair 6
  • Chromosomes, Human, Pair 9
  • DNA Repair Enzymes
  • DNA-Binding Proteins
  • European Continental Ancestry Group
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Kruppel-Like Transcription Factors
  • Linkage Disequilibrium
  • Logistic Models
  • Middle Aged
  • Odds Ratio
  • Polymorphism, Single Nucleotide
  • Quality Control
  • Risk Factors
  • Surveys and Questionnaires
  • United Kingdom
  • Comparative Study
  • Journal Article
  • Research Support, Non-U.S. Gov't

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