Evidence for a link between TNFRSF11A and risk of breast cancer

• DOI: 10.1007/s10549-011-1546-7
• Publication Date: 2011-05-03T07:01:35Z
• Authors: Núria Bonifaci; Marta Palafox; Pasquale Pellegrini; Ana Osorio; Javier Benítez; Paolo Peterlongo; Siranoush Manoukian; Bernard Peissel; Daniela Zaffaroni; Gaia Roversi; Monica Barile; Alessandra Viel; Frederique Mariette; Loris Bernard; Paolo Radice; Bella Kaufman; Yael Laitman; Roni Milgrom; Eitan Friedman; María E. Sáez; Fina Climent; María Teresa Soler; Orland Diez; Judith Balmaña; Adriana Lasa; Teresa Ramón y Cajal; María-Dolores Mir...; Miguel de la Hoya; Pedro Pérez-Segura; Trinidad Caldés; Víctor Moreno; Ander Urruticoechea; Joan Brunet; Conxi Lázaro; Ignacio Blanco; Miguel Angel Pujana; Eva González-Suárez
• Keywords: BRCA2 Protein; 0301 basic medicine; Heterozygote; BRCA1/2 mutation carriers; Receptor Activator of Nuclear Factor-kappa B; BRCA1 Protein; Genome-Wide Association; Colorectal-Cancer; Differentiation; Susceptibility; Ligand; Rankl; Bone; Osteoclastogenesis; Proliferation; Resolution; TNFRSF11A; Breast Neoplasms; RANK; 3. Good health; Cohort Studies; 03 medical and health sciences; Breast cancer; Mutation; Odds Ratio; Humans; Female; Genetic Predisposition to Disease

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.