Gene-gene interactions in breast cancer susceptibility

Clare Turnbull, Sheila Seal, Anthony Renwick, Margaret Warren-Perry, Deborah Hughes, Anna Elliott, David Pernet, Susan Peock, Julian W Adlard, Julian Barwell, Jonathan Berg, Angela F Brady, Carole Brewer, Glen Brice, Cyril Chapman, Jackie Cook, Rosemarie Davidson, Alan Donaldson, Fiona Douglas, Lynn GreenhalghAlex Henderson, Louise Izatt, Ajith Kumar, Fiona Lalloo, Zosia Miedzybrodzka, Patrick J Morrison, Joan Paterson, Mary Porteous, Mark T Rogers, Susan Shanley, Lisa Walker, Munaza Ahmed, Diana Eccles, D Gareth Evans, Peter Donnelly, Douglas F Easton, Michael R Stratton, Nazneen Rahman, Breast Cancer Susceptibility Collaboration (UK), EMBRACE

Research output: Contribution to journalArticlepeer-review

33 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)958-962
Number of pages5
JournalHuman Molecular Genetics
Issue number4
Early online date9 Nov 2011
Publication statusPublished - 15 Feb 2012


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