title: Gene-gene interactions in breast cancer susceptibility.
abstract: 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.
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK. clare.turnbull@icr.ac.uk
authors.forename: Clare
authors.initials: C
authors.lastname: Turnbull
authors.forename: Sheila
authors.initials: S
authors.lastname: Seal
authors.forename: Anthony
authors.initials: A
authors.lastname: Renwick
authors.forename: Margaret
authors.initials: M
authors.lastname: Warren-Perry
authors.forename: Deborah
authors.initials: D
authors.lastname: Hughes
authors.forename: Anna
authors.initials: A
authors.lastname: Elliott
authors.forename: David
authors.initials: D
authors.lastname: Pernet
authors.forename: Susan
authors.initials: S
authors.lastname: Peock
authors.forename: Julian W
authors.initials: JW
authors.lastname: Adlard
authors.forename: Julian
authors.initials: J
authors.lastname: Barwell
authors.forename: Jonathan
authors.initials: J
authors.lastname: Berg
authors.forename: Angela F
authors.initials: AF
authors.lastname: Brady
authors.forename: Carole
authors.initials: C
authors.lastname: Brewer
authors.forename: Glen
authors.initials: G
authors.lastname: Brice
authors.forename: Cyril
authors.initials: C
authors.lastname: Chapman
authors.forename: Jackie
authors.initials: J
authors.lastname: Cook
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Davidson
authors.forename: Alan
authors.initials: A
authors.lastname: Donaldson
authors.forename: Fiona
authors.initials: F
authors.lastname: Douglas
authors.forename: Lynn
authors.initials: L
authors.lastname: Greenhalgh
authors.forename: Alex
authors.initials: A
authors.lastname: Henderson
authors.forename: Louise
authors.initials: L
authors.lastname: Izatt
authors.forename: Ajith
authors.initials: A
authors.lastname: Kumar
authors.forename: Fiona
authors.initials: F
authors.lastname: Lalloo
authors.forename: Zosia
authors.initials: Z
authors.lastname: Miedzybrodzka
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Morrison
authors.forename: Joan
authors.initials: J
authors.lastname: Paterson
authors.forename: Mary
authors.initials: M
authors.lastname: Porteous
authors.forename: Mark T
authors.initials: MT
authors.lastname: Rogers
authors.forename: Susan
authors.initials: S
authors.lastname: Shanley
authors.forename: Lisa
authors.initials: L
authors.lastname: Walker
authors.forename: Munaza
authors.initials: M
authors.lastname: Ahmed
authors.forename: Diana
authors.initials: D
authors.lastname: Eccles
authors.forename: D Gareth
authors.initials: DG
authors.lastname: Evans
authors.forename: Peter
authors.initials: P
authors.lastname: Donnelly
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.forename: Nazneen
authors.initials: N
authors.lastname: Rahman
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D064447:Checkpoint Kinase 2; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005192:Family Health; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008957:Models, Genetic; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D006113:United Kingdom
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases
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