title: Modification of BRCA1-Associated Breast and Ovarian Cancer Risk by BRCA1-Interacting Genes.
abstract: Inherited BRCA1 mutations confer elevated cancer risk. Recent studies have identified genes that encode proteins that interact with BRCA1 as modifiers of BRCA1-associated breast cancer. We evaluated a comprehensive set of genes that encode most known BRCA1 interactors to evaluate the role of these genes as modifiers of cancer risk. A cohort of 2,825 BRCA1 mutation carriers was used to evaluate the association of haplotypes at ATM, BRCC36, BRCC45 (BRE), BRIP1 (BACH1/FANCJ), CTIP, ABRA1 (FAM175A), MERIT40, MRE11A, NBS1, PALB2 (FANCN), RAD50, RAD51, RAP80, and TOPBP1, and was associated with time to breast and ovarian cancer diagnosis. Statistically significant false discovery rate (FDR) adjusted P values for overall association of haplotypes (P(FDR)) with breast cancer were identified at ATM (P(FDR) = 0.029), BRCC45 (P(FDR) = 0.019), BRIP1 (P(FDR) = 0.008), CTIP (P(FDR) = 0.017), MERIT40 (P(FDR) = 0.019), NBS1 (P(FDR) = 0.003), RAD50 (P(FDR) = 0.014), and TOPBP1 (P(FDR) = 0.011). Haplotypes at ABRA1 (P(FDR) = 0.007), BRCC45 (P(FDR) = 0.016 and P(FDR) = 0.005 in two haplotype blocks), and RAP80 (P(FDR) < 0.001) were associated with ovarian cancer risk. Overall, the data suggest that genomic variation at multiple loci that encode proteins that interact biologically with BRCA1 are associated with modified breast cancer and ovarian cancer risk in women who carry BRCA1 mutations.
authors.affiliation: Abramson Cancer Center, Center for Clinical Epidemiology and Biostatistics, and Department of Medicine, The University of Pennsylvania Perleman School of Medicine, Philadelphia, Pennsylvania, USA. rebbeck@upenn.edu
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Rebbeck
authors.forename: Nandita
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authors.lastname: Mitra
authors.forename: Susan M
authors.initials: SM
authors.lastname: Domchek
authors.forename: Fei
authors.initials: F
authors.lastname: Wan
authors.forename: Tara M
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authors.lastname: Friebel
authors.forename: Teo V
authors.initials: TV
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authors.forename: Christian F
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authors.lastname: Singer
authors.forename: Muy-Kheng Maria
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authors.lastname: Tea
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Blum
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authors.lastname: Tung
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authors.lastname: Olopade
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authors.lastname: Weitzel
authors.forename: Henry T
authors.initials: HT
authors.lastname: Lynch
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Snyder
authors.forename: Judy E
authors.initials: JE
authors.lastname: Garber
authors.forename: Antonis C
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authors.lastname: Antoniou
authors.forename: Susan
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authors.lastname: Peock
authors.forename: D Gareth
authors.initials: DG
authors.lastname: Evans
authors.forename: Joan
authors.initials: J
authors.lastname: Paterson
authors.forename: M John
authors.initials: MJ
authors.lastname: Kennedy
authors.forename: Alan
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authors.lastname: Donaldson
authors.forename: Huw
authors.initials: H
authors.lastname: Dorkins
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Rubinstein
authors.forename: Mary B
authors.initials: MB
authors.lastname: Daly
authors.forename: Claudine
authors.initials: C
authors.lastname: Isaacs
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
authors.forename: Irene L
authors.initials: IL
authors.lastname: Andrulis
authors.forename: Eitan
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authors.lastname: Freidman
authors.forename: Yael
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authors.lastname: Laitman
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Ganz
authors.forename: Gail E
authors.initials: GE
authors.lastname: Tomlinson
authors.forename: Susan L
authors.initials: SL
authors.lastname: Neuhausen
authors.forename: Steven A
authors.initials: SA
authors.lastname: Narod
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Phelan
authors.forename: Roger
authors.initials: R
authors.lastname: Greenberg
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D056426:Genetic Loci; D014644:Genetic Variation; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D010051:Ovarian Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D012306:Risk; D055815:Young Adult
chemical_list: D019313:BRCA1 Protein