title: Association of death receptor 4 variant (683A > C) with ovarian cancer risk in BRCA1 mutation carriers.
abstract: Dysregulation of apoptosis plays an important role in carcinogenesis. Therefore, apoptosis-associated genes like the death receptor 4 (DR4, TRAIL-R1) are interesting candidates for modifying the penetrance of breast and ovarian cancer in carriers of BRCA1 and BRCA2 mutations. The DR-4 haplotype 626C-683C [626C > G, Thr209Arg (rs4871857) and 683A > C, Glu228Ala (rs17088993)] has recently been linked to an increased risk of breast cancer. To evaluate whether DR4 626C > G or DR4 683A > C modifies the risk of breast or ovarian cancer in carriers of BRCA1 and BRCA2 mutations, we undertook a national multicenter study including data of 840 carriers of breast cancer gene (BRCA) mutations. DNA samples were collected from 12 German research centers between 1996 and 2005 and were genotyped by the Taqman allelic discrimination assay. The association between genotypes and incidence of breast or ovarian cancer data was evaluated using a Cox proportional hazards regression model. We found evidence for a significant association of DR4 683A > C with a higher risk for ovarian cancer in carriers of BRCA1 mutations [n = 557, hazard ratio 1.78 (1.24-2.55), p = 0.009]. Our results thus indicate that the DR4 683A > C variant modifies the risk of ovarian cancer in carriers of BRCA1 mutations.
authors.affiliation: Department of Gynecology and Obstetrics, Center for Integrated Oncology (CIO), Center for Familial Breast and Ovarian Cancer, University of Cologne, Cologne, Germany.
authors.forename: Michelle G
authors.initials: MG
authors.lastname: Dick
authors.forename: Beatrix
authors.initials: B
authors.lastname: Versmold
authors.forename: Christoph
authors.initials: C
authors.lastname: Engel
authors.forename: Alfons
authors.initials: A
authors.lastname: Meindl
authors.forename: Norbert
authors.initials: N
authors.lastname: Arnold
authors.forename: Raymonda
authors.initials: R
authors.lastname: Varon-Mateeva
authors.forename: Christian
authors.initials: C
authors.lastname: Sutter
authors.forename: Dieter
authors.initials: D
authors.lastname: Niederacher
authors.forename: Helmut
authors.initials: H
authors.lastname: Deissler
authors.forename: Sabine
authors.initials: S
authors.lastname: Preisler-Adams
authors.forename: Karin
authors.initials: K
authors.lastname: Kast
authors.forename: Dieter
authors.initials: D
authors.lastname: Schäfer
authors.forename: Dorothea
authors.initials: D
authors.lastname: Gadzicki
authors.forename: Wolfram
authors.initials: W
authors.lastname: Heinritz
authors.forename: Barbara
authors.initials: B
authors.lastname: Wappenschmidt
authors.forename: Rita K
authors.initials: RK
authors.lastname: Schmutzler
mesh_terms: D000293:Adolescent; D000483:Alleles; D024682:BRCA2 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C111164:BRAP protein, human; D044767:Ubiquitin-Protein Ligases