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 G. E. M. Ausems; Jacopo Azzollini; Emmanuelle Barouk-Simonet; Julian Barwell; Muriel Belotti; Javier Benitez; Andreas Berger; Ake Borg; Angela R. Bradbury; Joan Brunet; Saundra S. Buys; Trinidad Caldes; Maria A. Caligo; Ian Campbell; Sandrine M. Caputo; Jocelyne Chiquette; Kathleen B. M. Claes; J. Margriet Collee; Fergus J. Couch; Isabelle Coupier; Mary B. Daly; Rosemarie Davidson; Orland Diez; Susan M. Domchek; Alan Donaldson; Cecilia M. Dorfling; Ros Eeles; Lidia Feliubadalo; Lenka Foretova; Jeffrey Fowler; Encarna B. Gomez Garcia; GEMO Study Collaborators; HEBON; EMBRACE; Dezheng Huo

doi:10.1093/jnci/djy132

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 G. E. M. AusemsJacopo Azzollini, Emmanuelle Barouk-Simonet, Julian Barwell, Muriel Belotti, Javier Benitez, Andreas Berger, Ake Borg, Angela R. Bradbury, Joan Brunet, Saundra S. Buys, Trinidad Caldes, Maria A. Caligo, Ian Campbell, Sandrine M. Caputo, Jocelyne Chiquette, Kathleen B. M. Claes, J. Margriet Collee, Fergus J. Couch, Isabelle Coupier, Mary B. Daly, Rosemarie Davidson, Orland Diez, Susan M. Domchek, Alan Donaldson, Cecilia M. Dorfling, Ros Eeles, Lidia Feliubadalo, Lenka Foretova, Jeffrey Fowler, Encarna B. Gomez Garcia, GEMO Study Collaborators, HEBON, EMBRACE, Dezheng Huo^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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 height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided.

Results: Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m(2) increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer.

Conclusion: Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management.

Original language	English
Article number	132
Pages (from-to)	350-364
Number of pages	15
Journal	Journal of the National Cancer Institute
Volume	111
Issue number	4
DOIs	https://doi.org/10.1093/jnci/djy132
Publication status	Published - Apr 2019

Keywords

BIOLOGICAL PATHWAYS
DISEASE
EPIDEMIOLOGY
FAMILY
GENETIC-VARIANTS
IDENTIFICATION
INSULIN
LOCI
OBESITY
WEIGHT

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10.1093/jnci/djy132

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Qian, F., Wang, S., Mitchell, J., McGuffog, L., Barrowdale, D., Leslie, G., Oosterwijk, J. C., Chung, W. K., Evans, D. G., Engel, C., Kast, K., Aalfs, C. M., Adank, M. A., Adlard, J., Agnarsson, B. A., Aittomaki, K., Alducci, E., Andrulis, I. L., Arun, B. K., ... Huo, D. (2019). Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study. Journal of the National Cancer Institute, 111(4), 350-364. Article 132. https://doi.org/10.1093/jnci/djy132

@article{e652a17756514167bb1f54a660c0ca8a,

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

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 height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided.Results: Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m(2) increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer.Conclusion: Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management.",

keywords = "BIOLOGICAL PATHWAYS, DISEASE, EPIDEMIOLOGY, FAMILY, GENETIC-VARIANTS, IDENTIFICATION, INSULIN, LOCI, OBESITY, WEIGHT",

author = "Frank Qian and Shengfeng Wang and Jonathan Mitchell and Lesley McGuffog and Daniel Barrowdale and Goska Leslie and Oosterwijk, {Jan C.} and Chung, {Wendy K.} and Evans, {D. Gareth} and Christoph Engel and Karin Kast and Aalfs, {Cora M.} and Adank, {Muriel A.} and Julian Adlard and Agnarsson, {Bjarni A.} and Kristiina Aittomaki and Elisa Alducci and Andrulis, {Irene L.} and Arun, {Banu K.} and Ausems, {Margreet G. E. M.} and Jacopo Azzollini and Emmanuelle Barouk-Simonet and Julian Barwell and Muriel Belotti and Javier Benitez and Andreas Berger and Ake Borg and Bradbury, {Angela R.} and Joan Brunet and Buys, {Saundra S.} and Trinidad Caldes and Caligo, {Maria A.} and Ian Campbell and Caputo, {Sandrine M.} and Jocelyne Chiquette and Claes, {Kathleen B. M.} and Collee, {J. Margriet} and Couch, {Fergus J.} and Isabelle Coupier and Daly, {Mary B.} and Rosemarie Davidson and Orland Diez and Domchek, {Susan M.} and Alan Donaldson and Dorfling, {Cecilia M.} and Ros Eeles and Lidia Feliubadalo and Lenka Foretova and Jeffrey Fowler and {Gomez Garcia}, {Encarna B.} and {GEMO Study Collaborators} and HEBON and EMBRACE and Dezheng Huo",

note = "Funding Information: 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{\textquoteright}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 Funding Information: (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 Qu{\'e}bec, and The Quebec Breast Cancer Foundation. Funding Information: 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. Funding Information: Dani{\`e}le Muller. Institut Bergoni{\'e}, Bordeaux, France: Emmanuelle Barouk-Simonet, Franc¸oise Bonnet, Virginie Bubien, Michel Longy, Nicolas Sevenet. Institut Claudius Regaud, Toulouse, France: Laurence Gladieff, Rosine Guimbaud, Viviane Feillel, Christine Toulas. CHU Grenoble, France: H{\'e}l{\`e}ne Dreyfus, Christine Dominique Leroux, Magalie Peysselon, Rebischung. CHU Dijon, France: Amandine Baurand, Geoffrey Bertolone, Fanny Coron, Laurence Faivre, Caroline Jacquot, Sarab Lizard. CHU St-Etienne, France: Caroline Kientz, Marine Lebrun, Fabienne Prieur. H{\^o}tel Dieu Centre Hospitalier, Chamb{\'e}ry, France: Sandra Fert Ferrer. Centre Antoine Lacassagne, Nice, France: V{\'e}ronique Mari. CHU Limoges, France: Laurence V{\'e}nat-Bouvet. CHU Nantes, France: St{\'e}phane B{\'e}zieau, Capucine Delnatte. CHU Bretonneau, Tours and Centre Hospitalier de Bourges France: Isabelle Mortemousque. Groupe Hospitalier Piti{\'e}-Salp{\'e}tri{\`e}re, Paris, France: Chrystelle Colas, Florence Coulet, Florent Soubrier, Mathilde Warcoin. CHU Vandoeuvre-les-Nancy, France: Myriam Bronner, Johanna Sokolowska. CHU Besanc¸on, France: Marie-Agn{\`e}s Collonge-Rame, Alexandre Damette. CHU Poitiers, Centre Hospitalier d{\textquoteright}Angoul{\^e}me and Centre Hospitalier de Niort, France: Paul Gesta. Centre Hospitalier de La Rochelle: Hakima Lallaoui. CHU N{\^i}mes Car{\'e}meau, France: Jean Chiesa. CHI Poissy, France: Denise Molina-Gomes. CHU Angers, France: Olivier Ingster; Ilse Coene and Brecht Crombez; Alicia Tosar and Paula Diaque; Drs Sofia Khan, Taru A. Muranen, Carl Blomqvist, Irja Erkkila€, and Virpi Palola. The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centers: Coordinating center: Netherlands Cancer Institute, Amsterdam, NL: M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, S. Verhoef, M.K. Schmidt, N.S. Russell, D.J. Jenner; Erasmus Medical Center, Rotterdam, NL: J.M. Coll{\'e}e, A.M.W. van den Ouweland, M.J. Hooning, C. Seynaeve, C.H.M. van Deurzen, I.M. Obdeijn; Leiden University Medical Center, NL: C.J. van Asperen, J.T. Wijnen, R.A.E.M. Tollenaar, P. Devilee, T.C.T.E.F. van Cronenburg; Radboud University Nijmegen Medical Center, NL: C.M. Kets, A.R. Mensenkamp; University Medical Center Utrecht, NL: M.G.E.M. Ausems, R.B. van der Luijt, C.C. van der Pol; Amsterdam Medical Center, NL: C.M. Aalfs, T.A.M. van Os; VU University Medical Center, Amsterdam, NL: J.J.P. Gille, Q. Waisfisz, H.E.J. Meijers-Heijboer; University Hospital Maastricht, NL: E.B. G{\'o}mez-Garcia, M.J. Blok; University Medical Center Groningen, NL: J.C. Oosterwijk, A.H. van der Hout, M.J. Mourits, G.H. de Bock; The Netherlands Foundation for the Detection of Hereditary Tumors, Leiden, NL: H.F. Vasen; The Netherlands Comprehensive Cancer Organization (IKNL): S. Siesling, J.Verloop; The Dutch Pathology Registry (PALGA): L.I.H. Overbeek; Hong Kong Sanatorium and Hospital; the Hungarian Breast and Ovarian Cancer Study Group members (Janos Papp, Aniko Bozsik, Timea Pocza, Zoltan Matrai, Miklos Kasler, Judit Franko, Maria Balogh, Gabriella Domokos, Judit Ferenczi, Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary) and the clinicians and patients for their contributions to this study; the Oncogenetics Group (VHIO) and the High Risk and Cancer Prevention Unit of the University Hospital Vall d{\textquoteright}Hebron, and the Cellex Foundation for providing research facilities and equipment; the ICO Hereditary Cancer Program team led by Dr Gabriel Capella; Dr Martine Dumont for sample management and skillful assistance; Ana Peixoto, Catarina Santos, and Pedro Pinto; members of the Center of Molecular Diagnosis, Oncogenetics Department and Molecular Oncology Research Center of Barretos Cancer Hospital; Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institutes of Health [USA]) for their contributions to this resource, and the many families who contribute to kConFab; the KOBRA Study Group; Csilla Szabo (National Human Genome Research Institute, National Institutes of Health, Bethesda, MD); Eva Machackova (Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Brno, Czech Republic); and Michal Zikan, Petr Pohlreich, and Zdenek Kleibl (Oncogynecologic Center and Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic); Anne Lincoln, Lauren Jacobs; the NICCC National Familial Cancer Consultation Service team led by Sara Dishon, the lab team led by Dr Flavio Lejbkowicz, and the research field operations team led by Dr Mila Pinchev; the investigators of the Australia New Zealand NRG Oncology group; members and participants in the Ontario Cancer Genetics Network; Leigha Senter, Kevin Sweet, Caroline Craven, Julia Cooper, and Michelle O{\textquoteright}Conor; Yip Cheng Har, Nur Aishah Mohd Taib, Phuah Sze Yee, Norhashimah Hassan, and all the research nurses, research assistants, and doctors involved in the MyBrCa Study for assistance in patient recruitment, data collection, and sample preparation; Philip Iau, Sng Jen-Hwei, and Sharifah Nor Akmal for contributing samples from the Singapore Breast Cancer Study and the HUKM-HKL Study, respectively; the Meirav Breast Center team at the Sheba Medical Center; H{\aa}kan Olsson, Helena Jernstr{\"o}m, Karin Henriksson, Katja Harbst, Maria Soller, Ulf Kristoffersson; from Gothenburg Sahlgrenska University Hospital: Anna Ofverholm,€ Margareta Nordling, Per Karlsson, Zakaria Einbeigi; from Stockholm and Karolinska University Hospital: Anna von Wachenfeldt, Annelie Liljegren, Annika Lindblom, Brita Arver, Gisela Barbany Bustinza; from Ume{\aa} University Hospital: Beatrice Melin, Christina Edwinsdotter Ardnor, Monica Emanuelsson; from Uppsala University: Hans Ehrencrona, Maritta Hellstr{\"o}m Pigg, Richard Rosenquist; from Link{\"o}ping University Hospital: Marie Stenmark-Askmalm, Sigrun Liedgren; Cecilia Zvocec, Qun Niu; Joyce Seldon and Lorna Kwan; Dr Robert Nussbaum, Beth Crawford, Kate Loranger, Julie Mak, Nicola Stewart, Robin Lee, Amie Blanco and Peggy Conrad and Salina Chan; Simon Gayther, Paul Pharoah, Carole Pye, Patricia Harrington, and Eva Wozniak; Geoffrey Lindeman, Marion Harris, Martin Delatycki, Sarah Sawyer, Rebecca Driessen, and Ella Thompson for performing all DNA amplification. Funding Information: 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{\textquoteright}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. Funding Information: 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 Madrile{\~n}a 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 Asociaci{\'o}n Espa{\~n}ola Contra el C{\'a}ncer (AECC), the Instituto de Salud Carlos III (organismo adscrito al Ministerio de Econom{\'i}a 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 Catal{\`a} de la Salut and Autonomous Government of Catalonia (2009SGR290, 2014SGR338, and PERIS Project MedPerCan). Asociaci{\'o}n Espa{\~n}ola Contra el C{\'a}ncer, Spanish Health Research Foundation, Carlos III Health Institute, organismo adscrito al Ministerio de Econom{\'i}a 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⨯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), MEYS— NPS 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. Funding Information: 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⨯1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects “5⨯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 Publisher Copyright: {\textcopyright} The Author(s) 2018. Published by Oxford University Press. All rights reserved.",

year = "2019",

month = apr,

doi = "10.1093/jnci/djy132",

language = "English",

volume = "111",

pages = "350--364",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "4",

}

Qian, F, Wang, S, Mitchell, J, McGuffog, L, Barrowdale, D, Leslie, G, Oosterwijk, JC, Chung, WK, Evans, DG, Engel, C, Kast, K, Aalfs, CM, Adank, MA, Adlard, J, Agnarsson, BA, Aittomaki, K, Alducci, E, Andrulis, IL, Arun, BK, Ausems, MGEM, Azzollini, J, Barouk-Simonet, E, Barwell, J, Belotti, M, Benitez, J, Berger, A, Borg, A, Bradbury, AR, Brunet, J, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Caputo, SM, Chiquette, J, Claes, KBM, Collee, JM, Couch, FJ, Coupier, I, Daly, MB, Davidson, R, Diez, O, Domchek, SM, Donaldson, A, Dorfling, CM, Eeles, R, Feliubadalo, L, Foretova, L, Fowler, J, Gomez Garcia, EB, GEMO Study Collaborators, HEBON, EMBRACE & Huo, D 2019, 'Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study', Journal of the National Cancer Institute, vol. 111, no. 4, 132, pp. 350-364. https://doi.org/10.1093/jnci/djy132

TY - JOUR

T1 - Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers

T2 - A Mendelian Randomization Study

AU - Qian, Frank

AU - Wang, Shengfeng

AU - Mitchell, Jonathan

AU - McGuffog, Lesley

AU - Barrowdale, Daniel

AU - Leslie, Goska

AU - Oosterwijk, Jan C.

AU - Chung, Wendy K.

AU - Evans, D. Gareth

AU - Engel, Christoph

AU - Kast, Karin

AU - Aalfs, Cora M.

AU - Adank, Muriel A.

AU - Adlard, Julian

AU - Agnarsson, Bjarni A.

AU - Aittomaki, Kristiina

AU - Alducci, Elisa

AU - Andrulis, Irene L.

AU - Arun, Banu K.

AU - Ausems, Margreet G. E. M.

AU - Azzollini, Jacopo

AU - Barouk-Simonet, Emmanuelle

AU - Barwell, Julian

AU - Belotti, Muriel

AU - Benitez, Javier

AU - Berger, Andreas

AU - Borg, Ake

AU - Bradbury, Angela R.

AU - Brunet, Joan

AU - Buys, Saundra S.

AU - Caldes, Trinidad

AU - Caligo, Maria A.

AU - Campbell, Ian

AU - Caputo, Sandrine M.

AU - Chiquette, Jocelyne

AU - Claes, Kathleen B. M.

AU - Collee, J. Margriet

AU - Couch, Fergus J.

AU - Coupier, Isabelle

AU - Daly, Mary B.

AU - Davidson, Rosemarie

AU - Diez, Orland

AU - Domchek, Susan M.

AU - Donaldson, Alan

AU - Dorfling, Cecilia M.

AU - Eeles, Ros

AU - Feliubadalo, Lidia

AU - Foretova, Lenka

AU - Fowler, Jeffrey

AU - Gomez Garcia, Encarna B.

AU - GEMO Study Collaborators

AU - HEBON

AU - EMBRACE

AU - Huo, Dezheng

N1 - Funding Information: 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 Funding Information: (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 Québec, and The Quebec Breast Cancer Foundation. Funding Information: 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. Funding Information: Danièle Muller. Institut Bergonié, Bordeaux, France: Emmanuelle Barouk-Simonet, Franc¸oise Bonnet, Virginie Bubien, Michel Longy, Nicolas Sevenet. Institut Claudius Regaud, Toulouse, France: Laurence Gladieff, Rosine Guimbaud, Viviane Feillel, Christine Toulas. CHU Grenoble, France: Hélène Dreyfus, Christine Dominique Leroux, Magalie Peysselon, Rebischung. CHU Dijon, France: Amandine Baurand, Geoffrey Bertolone, Fanny Coron, Laurence Faivre, Caroline Jacquot, Sarab Lizard. CHU St-Etienne, France: Caroline Kientz, Marine Lebrun, Fabienne Prieur. Hôtel Dieu Centre Hospitalier, Chambéry, France: Sandra Fert Ferrer. Centre Antoine Lacassagne, Nice, France: Véronique Mari. CHU Limoges, France: Laurence Vénat-Bouvet. CHU Nantes, France: Stéphane Bézieau, Capucine Delnatte. CHU Bretonneau, Tours and Centre Hospitalier de Bourges France: Isabelle Mortemousque. Groupe Hospitalier Pitié-Salpétrière, Paris, France: Chrystelle Colas, Florence Coulet, Florent Soubrier, Mathilde Warcoin. CHU Vandoeuvre-les-Nancy, France: Myriam Bronner, Johanna Sokolowska. CHU Besanc¸on, France: Marie-Agnès Collonge-Rame, Alexandre Damette. CHU Poitiers, Centre Hospitalier d’Angoulême and Centre Hospitalier de Niort, France: Paul Gesta. Centre Hospitalier de La Rochelle: Hakima Lallaoui. CHU Nîmes Carémeau, France: Jean Chiesa. CHI Poissy, France: Denise Molina-Gomes. CHU Angers, France: Olivier Ingster; Ilse Coene and Brecht Crombez; Alicia Tosar and Paula Diaque; Drs Sofia Khan, Taru A. Muranen, Carl Blomqvist, Irja Erkkila€, and Virpi Palola. The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centers: Coordinating center: Netherlands Cancer Institute, Amsterdam, NL: M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, S. Verhoef, M.K. Schmidt, N.S. Russell, D.J. Jenner; Erasmus Medical Center, Rotterdam, NL: J.M. Collée, A.M.W. van den Ouweland, M.J. Hooning, C. Seynaeve, C.H.M. van Deurzen, I.M. Obdeijn; Leiden University Medical Center, NL: C.J. van Asperen, J.T. Wijnen, R.A.E.M. Tollenaar, P. Devilee, T.C.T.E.F. van Cronenburg; Radboud University Nijmegen Medical Center, NL: C.M. Kets, A.R. Mensenkamp; University Medical Center Utrecht, NL: M.G.E.M. Ausems, R.B. van der Luijt, C.C. van der Pol; Amsterdam Medical Center, NL: C.M. Aalfs, T.A.M. van Os; VU University Medical Center, Amsterdam, NL: J.J.P. Gille, Q. Waisfisz, H.E.J. Meijers-Heijboer; University Hospital Maastricht, NL: E.B. Gómez-Garcia, M.J. Blok; University Medical Center Groningen, NL: J.C. Oosterwijk, A.H. van der Hout, M.J. Mourits, G.H. de Bock; The Netherlands Foundation for the Detection of Hereditary Tumors, Leiden, NL: H.F. Vasen; The Netherlands Comprehensive Cancer Organization (IKNL): S. Siesling, J.Verloop; The Dutch Pathology Registry (PALGA): L.I.H. Overbeek; Hong Kong Sanatorium and Hospital; the Hungarian Breast and Ovarian Cancer Study Group members (Janos Papp, Aniko Bozsik, Timea Pocza, Zoltan Matrai, Miklos Kasler, Judit Franko, Maria Balogh, Gabriella Domokos, Judit Ferenczi, Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary) and the clinicians and patients for their contributions to this study; the Oncogenetics Group (VHIO) and the High Risk and Cancer Prevention Unit of the University Hospital Vall d’Hebron, and the Cellex Foundation for providing research facilities and equipment; the ICO Hereditary Cancer Program team led by Dr Gabriel Capella; Dr Martine Dumont for sample management and skillful assistance; Ana Peixoto, Catarina Santos, and Pedro Pinto; members of the Center of Molecular Diagnosis, Oncogenetics Department and Molecular Oncology Research Center of Barretos Cancer Hospital; Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institutes of Health [USA]) for their contributions to this resource, and the many families who contribute to kConFab; the KOBRA Study Group; Csilla Szabo (National Human Genome Research Institute, National Institutes of Health, Bethesda, MD); Eva Machackova (Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Brno, Czech Republic); and Michal Zikan, Petr Pohlreich, and Zdenek Kleibl (Oncogynecologic Center and Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic); Anne Lincoln, Lauren Jacobs; the NICCC National Familial Cancer Consultation Service team led by Sara Dishon, the lab team led by Dr Flavio Lejbkowicz, and the research field operations team led by Dr Mila Pinchev; the investigators of the Australia New Zealand NRG Oncology group; members and participants in the Ontario Cancer Genetics Network; Leigha Senter, Kevin Sweet, Caroline Craven, Julia Cooper, and Michelle O’Conor; Yip Cheng Har, Nur Aishah Mohd Taib, Phuah Sze Yee, Norhashimah Hassan, and all the research nurses, research assistants, and doctors involved in the MyBrCa Study for assistance in patient recruitment, data collection, and sample preparation; Philip Iau, Sng Jen-Hwei, and Sharifah Nor Akmal for contributing samples from the Singapore Breast Cancer Study and the HUKM-HKL Study, respectively; the Meirav Breast Center team at the Sheba Medical Center; Håkan Olsson, Helena Jernström, Karin Henriksson, Katja Harbst, Maria Soller, Ulf Kristoffersson; from Gothenburg Sahlgrenska University Hospital: Anna Ofverholm,€ Margareta Nordling, Per Karlsson, Zakaria Einbeigi; from Stockholm and Karolinska University Hospital: Anna von Wachenfeldt, Annelie Liljegren, Annika Lindblom, Brita Arver, Gisela Barbany Bustinza; from Umeå University Hospital: Beatrice Melin, Christina Edwinsdotter Ardnor, Monica Emanuelsson; from Uppsala University: Hans Ehrencrona, Maritta Hellström Pigg, Richard Rosenquist; from Linköping University Hospital: Marie Stenmark-Askmalm, Sigrun Liedgren; Cecilia Zvocec, Qun Niu; Joyce Seldon and Lorna Kwan; Dr Robert Nussbaum, Beth Crawford, Kate Loranger, Julie Mak, Nicola Stewart, Robin Lee, Amie Blanco and Peggy Conrad and Salina Chan; Simon Gayther, Paul Pharoah, Carole Pye, Patricia Harrington, and Eva Wozniak; Geoffrey Lindeman, Marion Harris, Martin Delatycki, Sarah Sawyer, Rebecca Driessen, and Ella Thompson for performing all DNA amplification. Funding Information: 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. Funding Information: 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 Madrileña 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 Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III (organismo adscrito al Ministerio de Economía 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 Català de la Salut and Autonomous Government of Catalonia (2009SGR290, 2014SGR338, and PERIS Project MedPerCan). Asociación Española Contra el Cáncer, Spanish Health Research Foundation, Carlos III Health Institute, organismo adscrito al Ministerio de Economía 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⨯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), MEYS— NPS 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. Funding Information: 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⨯1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects “5⨯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 Publisher Copyright: © The Author(s) 2018. Published by Oxford University Press. All rights reserved.

PY - 2019/4

Y1 - 2019/4

N2 - 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 height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided.Results: Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m(2) increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer.Conclusion: Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management.

AB - 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 height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided.Results: Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m(2) increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer.Conclusion: Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management.

KW - BIOLOGICAL PATHWAYS

KW - DISEASE

KW - EPIDEMIOLOGY

KW - FAMILY

KW - GENETIC-VARIANTS

KW - IDENTIFICATION

KW - INSULIN

KW - LOCI

KW - OBESITY

KW - WEIGHT

U2 - 10.1093/jnci/djy132

DO - 10.1093/jnci/djy132

M3 - Article

C2 - 30312457

SN - 0027-8874

VL - 111

SP - 350

EP - 364

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

IS - 4

M1 - 132

ER -

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

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