TY - JOUR
T1 - Modification of ovarian cancer risk by BRCA1/2-interacting genes in a multicenter cohort of BRCA1/2 mutation carriers
AU - Rebbeck, Timothy R.
AU - Mitra, Nandita
AU - Domchek, Susan M.
AU - Wan, Fei
AU - Chuai, Shannon
AU - Friebel, Tara M.
AU - Panossian, Saarene
AU - Spurdle, Amanda
AU - Chenevix-Trench, Georgia
AU - Singer, Christian F.
AU - Pfeiler, Georg
AU - Neuhausen, Susan L.
AU - Lynch, Henry T.
AU - Garber, Judy E.
AU - Weitzel, Jeffrey N.
AU - Isaacs, Claudine
AU - Couch, Fergus
AU - Narod, Steven A.
AU - Rubinstein, Wendy S.
AU - Tomlinson, Gail E.
AU - Ganz, Patricia A.
AU - Olopade, Olufunmilayo I.
AU - Tung, Nadine
AU - Blum, Joanne L.
AU - Greenberg, Roger
AU - Nathanson, Katherine L.
AU - Daly, Mary B.
PY - 2009/7/15
Y1 - 2009/7/15
N2 - 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 (Pcorr = 0.007). At NBS1, we observed a Pcorr = 0.024 for haplotypes. In BRCA2 carriers, no associations were observed with CTIP, NBS1, RAD50, or TOPBP1. Rare haplotypes at ATM (Pcorr = 0.044) and BARD1 (Pcorr = 0.012) were associated with ovarian cancer risk. At BRIP1, two common haplotypes were significantly associated with ovarian cancer risk (Pcorr = 0.011). At MRE11, we observed a significant haplotype association (Pcorr = 0.012), and at RAD51, one common haplotype was significantly associated with ovarian cancer risk (Pcorr = 0.026). Variants in genes that interact biologically with BRCA1 and/or BRCA2 may be associated with modified ovarian cancer risk in women who carry BRCA1/2 mutations.
AB - 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 (Pcorr = 0.007). At NBS1, we observed a Pcorr = 0.024 for haplotypes. In BRCA2 carriers, no associations were observed with CTIP, NBS1, RAD50, or TOPBP1. Rare haplotypes at ATM (Pcorr = 0.044) and BARD1 (Pcorr = 0.012) were associated with ovarian cancer risk. At BRIP1, two common haplotypes were significantly associated with ovarian cancer risk (Pcorr = 0.011). At MRE11, we observed a significant haplotype association (Pcorr = 0.012), and at RAD51, one common haplotype was significantly associated with ovarian cancer risk (Pcorr = 0.026). Variants in genes that interact biologically with BRCA1 and/or BRCA2 may be associated with modified ovarian cancer risk in women who carry BRCA1/2 mutations.
KW - Acid Anhydride Hydrolases
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Ataxia Telangiectasia Mutated Proteins
KW - BRCA1 Protein/genetics
KW - BRCA2 Protein/genetics
KW - Carrier Proteins/genetics
KW - Cell Cycle Proteins/genetics
KW - DNA Repair Enzymes/genetics
KW - DNA-Binding Proteins/genetics
KW - Endodeoxyribonucleases
KW - Fanconi Anemia Complementation Group Proteins
KW - Female
KW - Gene Frequency
KW - Genotype
KW - Haplotypes
KW - Heterozygote
KW - Humans
KW - MRE11 Homologue Protein
KW - Middle Aged
KW - Mutation
KW - Nuclear Proteins/genetics
KW - Ovarian Neoplasms/genetics
KW - Polymorphism, Single Nucleotide
KW - Protein Serine-Threonine Kinases/genetics
KW - RNA Helicases/genetics
KW - Rad51 Recombinase/genetics
KW - Risk Factors
KW - Tumor Suppressor Proteins/genetics
KW - Ubiquitin-Protein Ligases/genetics
UR - http://www.scopus.com/inward/record.url?scp=67651000083&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-09-0625
DO - 10.1158/0008-5472.CAN-09-0625
M3 - Article
C2 - 19584272
SN - 0008-5472
VL - 69
SP - 5801
EP - 5810
JO - Cancer Research
JF - Cancer Research
IS - 14
ER -
