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Evidence for a link between TNFRSF11A and risk of breast cancer

  • 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 Miramar
  • Miguel de la Hoya
  • Pedro Pérez-Segura
  • Trinidad Caldés
  • Víctor Moreno
  • Ander Urruticoechea
  • Joan Brunet
  • Conxi Lázaro
  • Ignacio Blanco
  • Miguel Angel PujanaEmail author
  • Eva González-SuárezEmail author
Epidemiology

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 (wHR) = 0.70; 95% CI 0.55–0.88; and P trend = 0.003; compared to BRCA1 mutation carriers, wHR = 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.

Keywords

Breast cancer BRCA1/2 mutation carriers RANK TNFRSF11A 

Notes

Acknowledgments

We wish to thank all study participants, clinicians, and centers for their valuable contributions, and the CGEMS initiative for making their genome-wide association study results available. The CONSIT TEAM thanks Marco A Pierotti, Carla B Ripamonti, and Marilena Morganti of the Fondazione IRCCS Istituto Nazionale dei Tumori, and Bernardo Bonanni of the Istituto Europeo di Oncologia. The authors acknowledge the following grants for support of this work: a 2009 Spanish Society of Medical Oncology grant to J. Brunet; Ramón Areces Foundation XV, FIS (09/02483), and Generalitat de Catalunya 2009-SGR283 grants to MAP; the Biomedical Research Center Network for Epidemiology and Public Health Group 55 to MAP and VM; the Spanish Association Against Cancer (AECC) and FIS (08/1120) grants to J. Benítez; the RTICC 06/0020/0021 to HCSC; and MICINN (SAF2008-01975), Concern Foundation, and Scientific Foundation of the Spanish Association Against Cancer grants to EG-S. The CONSIT TEAM is supported by grants from Ministero della Salute (Extraordinary National Cancer Program 2006 “Alleanza contro il Cancro” and “Progetto Tumori Femminili”), Ministero dell’Universita’ e Ricerca (RBLAO3-BETH to PR), Fondazione Italiana per la Ricerca sul Cancro (Special Project “Hereditary tumors”) to PR, Associazione Italiana per la Ricerca sul Cancro (4017) to PP, and by funds from Italian citizens who allocated the 5 × 1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, as provided for in Italian laws (INT institutional strategic projects “5 × 1000”).

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

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Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Núria Bonifaci
    • 1
  • Marta Palafox
    • 2
  • Pasquale Pellegrini
    • 2
  • Ana Osorio
    • 3
  • Javier Benítez
    • 3
  • Paolo Peterlongo
    • 4
  • Siranoush Manoukian
    • 5
  • Bernard Peissel
    • 5
  • Daniela Zaffaroni
    • 5
  • Gaia Roversi
    • 5
  • Monica Barile
    • 6
  • Alessandra Viel
    • 7
  • Frederique Mariette
    • 8
  • Loris Bernard
    • 9
  • Paolo Radice
    • 4
  • Bella Kaufman
    • 10
  • Yael Laitman
    • 11
  • Roni Milgrom
    • 11
  • Eitan Friedman
    • 11
    • 12
  • María E. Sáez
    • 13
  • Fina Climent
    • 14
  • María Teresa Soler
    • 14
  • Orland Diez
    • 15
  • Judith Balmaña
    • 16
  • Adriana Lasa
    • 17
  • Teresa Ramón y Cajal
    • 17
  • María-Dolores Miramar
    • 18
  • Miguel de la Hoya
    • 19
  • Pedro Pérez-Segura
    • 20
  • Trinidad Caldés
    • 19
  • Víctor Moreno
    • 1
  • Ander Urruticoechea
    • 21
  • Joan Brunet
    • 22
  • Conxi Lázaro
    • 23
  • Ignacio Blanco
    • 23
  • Miguel Angel Pujana
    • 1
    • 21
    Email author
  • Eva González-Suárez
    • 2
    Email author
  1. 1.Biomarkers and Susceptibility Unit, and Biomedical Research Center Network for Epidemiology and Public Health, Cancer Prevention and Control Program, Catalan Institute of OncologyBellvitge Institute for Biomedical Research (IDIBELL)BarcelonaSpain
  2. 2.Cancer Epigenetics and Biology Program (PEBC)Bellvitge Institute for Biomedical Research (IDIBELL)BarcelonaSpain
  3. 3.Human Cancer Genetics Program and Biomedical Research Center Network for Rare DiseasesSpanish National Cancer Research CentreMadridSpain
  4. 4.Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive MedicineFondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, and IFOM Fondazione Istituto FIRC di Oncologia MolecolareMilanItaly
  5. 5.Unit of Medical Genetics, Department of Preventive and Predictive MedicineFondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale TumoriMilanItaly
  6. 6.Division of Cancer Prevention and GeneticsIstituto Europeo di OncologiaMilanItaly
  7. 7.Division of Experimental Oncology 1Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere ScientificoAvianoItaly
  8. 8.Consortium for Genomics Technology (Cogentech)MilanItaly
  9. 9.Department of Experimental OncologyIstituto Europeo di OncologiaMilanItaly
  10. 10.The Institute of OncologyChaim Sheba Medical CenterRamat GanIsrael
  11. 11.The Susanne Levy Gertner Oncogenetics Unit, Institute of Human GeneticsChaim Sheba Medical CenterRamat GanIsrael
  12. 12.Sackler Faculty of MedicineTel Aviv UniversityRamat AvivIsrael
  13. 13.Department of Structural GenomicsNeocodexSevillaSpain
  14. 14.Department of PathologyUniversity Hospital of Bellvitge, Bellvitge Institute for Biomedical Research (IDIBELL)BarcelonaSpain
  15. 15.Vall d’Hebron Institute of OncologyUniversity Hospital Vall d’HebronBarcelonaSpain
  16. 16.Department of Medical OncologyUniversity Hospital Vall d’HebronBarcelonaSpain
  17. 17.Department of Medical OncologyHospital Santa Creu i Sant PauBarcelonaSpain
  18. 18.Genetics Unit, Clinical Biochemistry Service, Miguel ServetUniversity HospitalZaragozaSpain
  19. 19.Molecular Oncology LaboratoryHospital Clínico San CarlosMadridSpain
  20. 20.Medical OncologyHospital Clínico San CarlosMadridSpain
  21. 21.Translational Research Laboratory, Catalan Institute of OncologyBellvitge Institute for Biomedical Research (IDIBELL)BarcelonaSpain
  22. 22.Hereditary Cancer Program, Catalan Institute of OncologyGirona Biomedical Research InstituteGironaSpain
  23. 23.Hereditary Cancer Program, Catalan Institute of OncologyBellvitge Institute for Biomedical Research (IDIBELL)BarcelonaSpain

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