Journal article

Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study

Frank Qian, Shengfeng Wang, Jonathan Mitchell, Lesley McGuffog, Daniel Barrowdale, Goska Leslie, Jan C Oosterwijk, Wendy K Chung, D Gareth Evans, Christoph Engel, Karin Kast, Cora M Aalfs, Muriel A Adank, Julian Adlard, Bjarni A Agnarsson, Kristiina Aittomaki, Elisa Alducci, Irene L Andrulis, Banu K Arun, Margreet GEM Ausems Show all

JNCI: Journal of the National Cancer Institute | OXFORD UNIV PRESS INC | Published : 2019

Abstract

BACKGROUND: BRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 mutation carriers remains unclear. METHODS: We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants. We examined both observed and genetically determined..

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Grants

Awarded by Cancer Research - UK


Awarded by iCOGS: the European Community's Seventh Framework Programme


Awarded by Cancer Research UK


Awarded by National Institutes of Health


Awarded by Post-Cancer GWAS initiative (GAME-ON initiative)


Awarded by Department of Defence


Awarded by Canadian Institutes of Health Research (CIHR)


Awarded by Ministry of Economic Development, Innovation and Export Trade


Awarded by National Cancer Institute


Awarded by BFBOCC: Lithuania (BFBOCC-LT): Research Council of Lithuania


Awarded by FEDER funds


Awarded by Spanish Ministry of Economy and Competitiveness (MINECO)


Awarded by National Cancer Institute of the National Institutes of Health from the National Cancer Institute


Awarded by CONSIT: Associazione Italiana Ricerca sul Cancro (AIRC)


Awarded by Italian Association for Cancer Research (AIRC)


Awarded by Associazione Italiana Ricerca sul Cancro (AIRC)


Awarded by Greek national funds through the Operational Program " Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) -Research Funding Program of the General Secretariat for Research Technology


Awarded by EMBRACE: Cancer Research UK


Awarded by FCCC: The University of Kansas Cancer Center


Awarded by FPGMX


Awarded by GC-HBOC: German Cancer Aid


Awarded by Free State of Saxony, Germany (LIFE Leipzig Research Centre for Civilization Diseases)


Awarded by GEORGETOWN: the Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI)


Awarded by European Regional Development FEDER funds


Awarded by Academy of Finland


Awarded by HEBON: the Dutch Cancer Society


Awarded by Netherlands Organization of Scientific Research


Awarded by Pink Ribbon grants


Awarded by BBMRI


Awarded by Transcan grant JTC 2012 Cancer


Awarded by National Institute of Health


Awarded by HUNBOCS: Hungarian Research Grants


Awarded by Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa


Awarded by Autonomous Government of Catalonia


Awarded by IHCC


Awarded by INHERIT: Canadian Institutes of Health Research


Awarded by MAYO: NIH


Awarded by NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer


Awarded by European Union Seventh Framework Programme (2007Y2013)/European Research Council


Awarded by MODSQUAD: MH CZ-DRO (MMCI)


Awarded by Charles University in Prague project


Awarded by Cancer Center Support Grant/Core Grant


Awarded by NAROD


Awarded by Westat, Inc, Rockville, MD


Awarded by NNPIO: the Russian Federation for Basic Research


Awarded by NRG Oncology


Awarded by NRG SDMC grant


Awarded by NRG Tissue Bank


Awarded by NRG Statistical and Data Center


Awarded by PBCS: Italian Association of Cancer Research (AIRC)


Awarded by Tuscany Institute for Tumors (ITT) grant


Awarded by Ministry of Higher Education


Awarded by UCHICAGO: NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer


Awarded by American Cancer Society


Awarded by Susan G. Komen Foundation


Awarded by American Cancer Society Early Detection Professorship


Awarded by National Center for Advancing Translational Sciences (NCATS)


Awarded by NIH



Funding Acknowledgements

CIMBA: The CIMBA data management and data analysis were supported by Cancer Research - UK grants C12292/A20861, C12292/A11174. GCT and ABS are NHMRC Research Fellows. iCOGS: the European Community's Seventh Framework Programme under grant agreement No. 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065, and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer (CRN-87521), and the Ministry of Economic Development, Innovation and Export Trade (PSR-SIIRI-701), Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministry of Economy, Science and Innovation through Genome Quebec, and The Quebec Breast Cancer Foundation.BCFR: UM1 CA164920 from the National Cancer Institute. The content of this article does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR. BFBOCC: Lithuania (BFBOCC-LT): Research Council of Lithuania grant SEN-18/2015. BIDMC: Breast Cancer Research Foundation. BMBSA: Cancer Association of South Africa (PI Elizabeth J. van Rensburg). CNIO: Spanish Ministry of Health PI16/00440 supported by FEDER funds, the Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Research Network on Rare diseases (CIBERER). COH-CCGCRN: Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under grant number R25CA112486, and RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. CONSIT: Associazione Italiana Ricerca sul Cancro (AIRC; IG2014 no. 15547) to P. Radice. Italian Association for Cancer Research (AIRC; grant no. 16933) to L. Ottini. Associazione Italiana Ricerca sul Cancro (AIRC; IG2015 no. 16732) to P. Peterlongo. Jacopo Azzollini is supported by funds from Italian citizens who allocated the 5 x 1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects "5 x 1000"). DEMOKRITOS: European Union (European Social Fund -ESF) and Greek national funds through the Operational Program " Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) -Research Funding Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA. Investing in Knowledge Society through the European Social Fund. DFKZ: German Cancer Research Center. EMBRACE: Cancer Research UK Grants C1287/A10118 and C1287/A11990. DGE and FL are supported by an NIHR grant to the Biomedical Research Centre, Manchester, UK. The investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. Ros Eeles is also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. FCCC: The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. was funded by R0 1CA140323, R01 CA214545, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. FPGMX: FISPI05/2275 and Mutua Madrilena Foundation (FMMA). GC-HBOC: German Cancer Aid (grant no 110837, Rita K. Schmutzler) and the European Regional Development Fund and Free State of Saxony, Germany (LIFE Leipzig Research Centre for Civilization Diseases, project numbers 713-241202, 713-241202, 14505/2470, 14575/2470). GEMO: Ligue Nationale Contre le Cancer; the Association "Le cancer du sein, parlons-en!" Award, the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program, and the French National Institute of Cancer (INCa).GEORGETOWN: the Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008), the Fisher Center for Hereditary Cancer and Clinical Genomics Research, and Swing For the Cure. G-FAST: Bruce Poppe is a senior clinical investigator of FWO. Mattias Van Heetvelde obtained funding from IWT. HCSC: Spanish Ministry of Health PI15/00059, PI16/01292, and CB-161200301 CIBERONC from ISCIII (Spain), partially supported by European Regional Development FEDER funds. HEBCS: Helsinki University Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, and the Sigrid Juselius Foundation. HEBON: the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187. WO76, the BBMRI grant NWO 184.021.007/CP46, and the Transcan grant JTC 2012 Cancer 12-054. HEBON thanks the registration teams of Dutch Cancer Registry (IKNL; S. Siesling, J. Verloop) and the Dutch Pathology database (PALGA; L. Overbeek) for part of the data collection. HRBCP: Hong Kong Sanatorium and Hospital, Dr Ellen Li Charitable Foundation, The Kerry Group Kuok Foundation, National Institute of Health1R 03CA130065, and North California Cancer Center. HUNBOCS: Hungarian Research Grants KTIA-OTKA CK-80745 and OTKA K-112228. ICO: The authors would like to particularly acknowledge the support of the Asociacion Espanola Contra el Cancer (AECC), the Instituto de Salud Carlos III (organismo adscrito al Ministerio de Economia y Competitividad) and " Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa" (PI10/01422, PI13/00285, PIE13/00022, PI15/00854, PI16/00563, and CIBERONC), and the Institut Catala de la Salut and Autonomous Government of Catalonia (2009SGR290, 2014SGR338, and PERIS Project MedPerCan). Asociaci on Espanola Contra el Cancer, Spanish Health Research Foundation, Carlos III Health Institute, organismo adscrito al Ministerio de Economia y Competitividad, " Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa", Catalan Health Institute, and Autonomous Government of Catalonia (ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI13/00285, PIE13/00022, PI15/00854, PI16/00563, and 2009SGR283). IHCC: PBZ_ KBN_ 122/P05/2004. ILUH: Icelandic Association " Walking for Breast Cancer Research" and by the Landspitali University Hospital Research Fund. INHERIT: Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program (grant #CRN-87521) and the Ministry of Economic Development, Innovation and Export Trade (grant #PSR-SIIRI-701). IOVHBOCS: Ministero della Salute and " 5 x 1000" Istituto Oncologico Veneto grant. IPOBCS: Liga Portuguesa Contra o Cancro. kConFab: The National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, and the Cancer Foundation of Western Australia. MAYO: NIH grants CA116167, CA192393, and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), and a grant from the Breast Cancer Research Foundation. MCGILL: Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. MTi is supported by the European Union Seventh Framework Programme (2007Y2013)/European Research Council (Grant No. 310018).MODSQUAD: MH CZ-DRO (MMCI, 00209805), MEYSNPS I - LO1413 to LF, and by Charles University in Prague project UNCE204024 (MZ). MSKCC: the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, the Andrew Sabin Research Fund, and a Cancer Center Support Grant/Core Grant (P30 CA008748). NAROD: 1R01 CA149429-01. NCI: the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50, N02-CP-21013-63, and N02-CP-65504 with Westat, Inc, Rockville, MD. NICCC: Clalit Health Services in Israel, the Israel Cancer Association, and the Breast Cancer Research Foundation (BCRF), New Yotk, NY. NNPIO: the Russian Federation for Basic Research (grants 15-04-01744, 16-54-00055, 17-54-12007). NRG Oncology: U10 CA180868, NRG SDMC grant U10 CA180822, NRG Administrative Office and the NRG Tissue Bank (CA 27469), the NRG Statistical and Data Center (CA 37517), and the Intramural Research Program, NCI. OSUCCG: Ohio State University Comprehensive Cancer Center. PBCS: Italian Association of Cancer Research (AIRC) [IG 2013 N. 14477] and Tuscany Institute for Tumors (ITT) grant 2014-2015-2016. SEABASS: Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM. C/HlR/MOHE/06), and Cancer Research Initiatives Foundation. SMC: the Israeli Cancer Association. SWE-BRCA: the Swedish Cancer Society. UCHICAGO: NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032, American Cancer Society (MRSG-13-063-01-TBG, CRP-10-119-01-CCE), Breast Cancer Research Foundation, Susan G. Komen Foundation (SAC110026), and Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women's Cancer Research Alliance. UCLA: Jonsson Comprehensive Cancer Center Foundation; Breast Cancer Research Foundation. UCSF: UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center. UKFOCR: Cancer Research UK. UPENN: National Institutes of Health (NIH); Breast Cancer Research Foundation; Susan G. Komen Foundation for the Cure, Basser Center for BRCA. UPITT/MWH: Hackers for Hope Pittsburgh. VFCTG: Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation. WCP: Dr Karlan is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124. JM was supported by NIH grant F32CA162847.