title: Evidence for a link between TNFRSF11A and risk of breast cancer.
abstract: Intracellular signaling mediated by the receptor activator of nuclear factor-κB [Rank, encoded by the tumor necrosis factor receptor superfamily, member 11a (Tnfrsf11a) gene] is fundamental for mammary gland development in mice, regulating the expansion of stem and progenitor cell compartments. Conversely, Rank overexpression in mice promotes abnormal proliferation and impairs differentiation, leading to an increased incidence of tumorigenesis. Here, we show that a common genetic variant near the 5'-end of TNFRSF11A, rs7226991, is associated with breast cancer risk in the general population and among carriers of mutations in the breast cancer 2, early onset (BRCA2) gene. Akin to the results of the Cancer and Genetics Markers of Susceptibility initiative, combined analysis of rs7226991 in two Spanish case-control studies (1,365 controls and 1,323 cases in total) revealed a significant association with risk: odds ratio (OR) = 0.88, 95% confidence interval (CI) 0.78-0.98, P (trend) = 0.025. Subsequent examination of BRCA1 (n = 1,017) and BRCA2 (n = 885) mutation carriers revealed a consistent association in the latter group: weighted hazard ratio ((w)HR) = 0.70; 95% CI 0.55-0.88; and P (trend) = 0.003; compared to BRCA1 mutation carriers, (w)HR = 0.91; 95% CI 0.76-1.10; and P (trend) = 0.33. The results of this study need to be replicated in other populations and with larger numbers of BRCA1/2 mutation carriers.
authors.affiliation: Biomarkers and Susceptibility Unit, and Biomedical Research Center Network for Epidemiology and Public Health, Cancer Prevention and Control Program, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), Gran Via 199, L'Hospitalet, Barcelona 08908, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Bonifaci
authors.forename: Marta
authors.initials: M
authors.lastname: Palafox
authors.forename: Pasquale
authors.initials: P
authors.lastname: Pellegrini
authors.forename: Ana
authors.initials: A
authors.lastname: Osorio
authors.forename: Javier
authors.initials: J
authors.lastname: Benítez
authors.forename: Paolo
authors.initials: P
authors.lastname: Peterlongo
authors.forename: Siranoush
authors.initials: S
authors.lastname: Manoukian
authors.forename: Bernard
authors.initials: B
authors.lastname: Peissel
authors.forename: Daniela
authors.initials: D
authors.lastname: Zaffaroni
authors.forename: Gaia
authors.initials: G
authors.lastname: Roversi
authors.forename: Monica
authors.initials: M
authors.lastname: Barile
authors.forename: Alessandra
authors.initials: A
authors.lastname: Viel
authors.forename: Frederique
authors.initials: F
authors.lastname: Mariette
authors.forename: Loris
authors.initials: L
authors.lastname: Bernard
authors.forename: Paolo
authors.initials: P
authors.lastname: Radice
authors.forename: Bella
authors.initials: B
authors.lastname: Kaufman
authors.forename: Yael
authors.initials: Y
authors.lastname: Laitman
authors.forename: Roni
authors.initials: R
authors.lastname: Milgrom
authors.forename: Eitan
authors.initials: E
authors.lastname: Friedman
authors.forename: María E
authors.initials: ME
authors.lastname: Sáez
authors.forename: Fina
authors.initials: F
authors.lastname: Climent
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Soler
authors.forename: Orland
authors.initials: O
authors.lastname: Diez
authors.forename: Judith
authors.initials: J
authors.lastname: Balmaña
authors.forename: Adriana
authors.initials: A
authors.lastname: Lasa
authors.forename: Teresa
authors.initials: T
authors.lastname: Ramón y Cajal
authors.forename: María-Dolores
authors.initials: MD
authors.lastname: Miramar
authors.forename: Miguel
authors.initials: M
authors.lastname: de la Hoya
authors.forename: Pedro
authors.initials: P
authors.lastname: Pérez-Segura
authors.forename: Trinidad
authors.initials: T
authors.lastname: Caldés
authors.forename: Víctor
authors.initials: V
authors.lastname: Moreno
authors.forename: Ander
authors.initials: A
authors.lastname: Urruticoechea
authors.forename: Joan
authors.initials: J
authors.lastname: Brunet
authors.forename: Conxi
authors.initials: C
authors.lastname: Lázaro
authors.forename: Ignacio
authors.initials: I
authors.lastname: Blanco
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Pujana
authors.forename: Eva
authors.initials: E
authors.lastname: González-Suárez
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D016017:Odds Ratio; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human