Gene-gene interactions in breast cancer susceptibility

Breast Cancer Susceptibility Collaboration (UK), EMBRACE

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)


There have been few definitive examples of gene-gene interactions in humans. Through mutational analyses in 7325 individuals, we report four interactions (defined as departures from a multiplicative model) between mutations in the breast cancer susceptibility genes ATM and CHEK2 with BRCA1 and BRCA2 (case-only interaction between ATM and BRCA1/BRCA2 combined, P = 5.9 × 10(-4); ATM and BRCA1, P= 0.01; ATM and BRCA2, P= 0.02; CHEK2 and BRCA1/BRCA2 combined, P = 2.1 × 10(-4); CHEK2 and BRCA1, P= 0.01; CHEK2 and BRCA2, P= 0.01). The interactions are such that the resultant risk of breast cancer is lower than the multiplicative product of the constituent risks, and plausibly reflect the functional relationships of the encoded proteins in DNA repair. These findings have important implications for models of disease predisposition and clinical translation.

Original languageEnglish
Pages (from-to)958-62
Number of pages5
JournalHuman Molecular Genetics
Issue number4
Publication statusPublished - 15 Feb 2012


  • Ataxia Telangiectasia Mutated Proteins
  • Breast Neoplasms/genetics
  • Cell Cycle Proteins/genetics
  • Checkpoint Kinase 2
  • DNA Mutational Analysis
  • DNA-Binding Proteins/genetics
  • Family Health
  • Female
  • Genes, BRCA1
  • Genes, BRCA2
  • Genetic Predisposition to Disease/genetics
  • Humans
  • Models, Genetic
  • Pedigree
  • Protein-Serine-Threonine Kinases/genetics
  • Tumor Suppressor Proteins/genetics
  • United Kingdom


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