title: Modification of ovarian cancer risk by BRCA1/2-interacting genes in a multicenter cohort of BRCA1/2 mutation carriers.
abstract: Inherited BRCA1/2 mutations confer elevated ovarian cancer risk. Knowledge of factors that can improve ovarian cancer risk assessment in BRCA1/2 mutation carriers is important because no effective early detection for ovarian cancers exists. A cohort of 1,575 BRCA1 and 856 BRCA2 mutation carriers was used to evaluate haplotypes at ATM, BARD1, BRIP1, CTIP, MRE11, NBS1, RAD50, RAD51, and TOPBP1 in ovarian cancer risk. In BRCA1 carriers, no associations were observed with ATM, BARD1, CTIP, RAD50, RAD51, or TOPBP1. At BRIP1, an association was observed for one haplotype with a multiple testing corrected P (P(corr)) = 0.012, although no individual haplotype was significant. At MRE11, statistically significant associations were observed for one haplotype (P(corr) = 0.007). At NBS1, we observed a P(corr) = 0.024 for haplotypes. In BRCA2 carriers, no associations were observed with CTIP, NBS1, RAD50, or TOPBP1. Rare haplotypes at ATM (P(corr) = 0.044) and BARD1 (P(corr) = 0.012) were associated with ovarian cancer risk. At BRIP1, two common haplotypes were significantly associated with ovarian cancer risk (P(corr) = 0.011). At MRE11, we observed a significant haplotype association (P(corr) = 0.012), and at RAD51, one common haplotype was significantly associated with ovarian cancer risk (P(corr) = 0.026). Variants in genes that interact biologically withBRCA1 and/or BRCA2 may be associated with modified ovarian cancer risk in women who carry BRCA1/2 mutations.
authors: Abramson Cancer Center, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6021, USA. rebbeck@mail.med.upenn.edu
authors: Timothy R
authors: TR
authors: Rebbeck
authors: Nandita
authors: N
authors: Mitra
authors: Susan M
authors: SM
authors: Domchek
authors: Fei
authors: F
authors: Wan
authors: Shannon
authors: S
authors: Chuai
authors: Tara M
authors: TM
authors: Friebel
authors: Saarene
authors: S
authors: Panossian
authors: Amanda
authors: A
authors: Spurdle
authors: Georgia
authors: G
authors: Chenevix-Trench
authors: Christian F
authors: CF
authors: Singer
authors: Georg
authors: G
authors: Pfeiler
authors: Susan L
authors: SL
authors: Neuhausen
authors: Henry T
authors: HT
authors: Lynch
authors: Judy E
authors: JE
authors: Garber
authors: Jeffrey N
authors: JN
authors: Weitzel
authors: Claudine
authors: C
authors: Isaacs
authors: Fergus
authors: F
authors: Couch
authors: Steven A
authors: SA
authors: Narod
authors: Wendy S
authors: WS
authors: Rubinstein
authors: Gail E
authors: GE
authors: Tomlinson
authors: Patricia A
authors: PA
authors: Ganz
authors: Olufunmilayo I
authors: OI
authors: Olopade
authors: Nadine
authors: N
authors: Tung
authors: Joanne L
authors: JL
authors: Blum
authors: Roger
authors: R
authors: Greenberg
authors: Katherine L
authors: KL
authors: Nathanson
authors: Mary B
authors: MB
authors: Daly
mesh_terms: D017766:Acid Anhydride Hydrolases; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004706:Endodeoxyribonucleases; D051856:Fanconi Anemia Complementation Group Proteins; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D000076228:MRE11 Homologue Protein; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D020365:RNA Helicases / Q000235:genetics; D051135:Rad51 Recombinase / Q000235:genetics; D012307:Risk Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051856:Fanconi Anemia Complementation Group Proteins; C121766:MRE11 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; C110513:TOPBP1 protein, human; D025521:Tumor Suppressor Proteins; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D051135:Rad51 Recombinase; D004706:Endodeoxyribonucleases; D000076228:MRE11 Homologue Protein; C410741:RBBP8 protein, human; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; C000618935:BRIP1 protein, human; D020365:RNA Helicases; D045643:DNA Repair Enzymes