Modification of ovarian cancer risk by BRCA1/2-interacting genes in a multicenter cohort of BRCA1/2 mutation carriers.
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.
Rebbeck
Timothy R
TR
Abramson Cancer Center, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6021, USA. rebbeck@mail.med.upenn.edu
Mitra
Nandita
N
Domchek
Susan M
SM
Wan
Fei
F
Chuai
Shannon
S
Friebel
Tara M
TM
Panossian
Saarene
S
Spurdle
Amanda
A
Chenevix-Trench
Georgia
G
Singer
Christian F
CF
Pfeiler
Georg
G
Neuhausen
Susan L
SL
Lynch
Henry T
HT
Garber
Judy E
JE
Weitzel
Jeffrey N
JN
Isaacs
Claudine
C
Couch
Fergus
F
Narod
Steven A
SA
Rubinstein
Wendy S
WS
Tomlinson
Gail E
GE
Ganz
Patricia A
PA
Olopade
Olufunmilayo I
OI
Tung
Nadine
N
Blum
Joanne L
JL
Greenberg
Roger
R
Nathanson
Katherine L
KL
Daly
Mary B
MB
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
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