Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers

Frank Qian; Matti A. Rookus; Goska Leslie; Harvey A. Risch; Mark H. Greene; Cora M. Aalfs; Muriel A. Adank; Julian Adlard; Bjarni A. Agnarsson; Munaza Ahmed; Kristiina Aittomäki; Irene L. Andrulis; Norbert Arnold; Banu K. Arun; Margreet G. E. M. Ausems; Jacopo Azzollini; Daniel Barrowdale; Julian Barwell; Javier Benitez; Katarzyna Białkowska; Valérie Bonadona; Julika Borde; Ake Borg; Angela R. Bradbury; Joan Brunet; Saundra S. Buys; Trinidad Caldés; Maria A. Caligo; Ian Campbell; Jonathan Carter; Jocelyne Chiquette; Wendy K. Chung; Kathleen B. M. Claes; J. Margriet Collée; Marie-Agnès Collonge-Rame; Fergus J. Couch; Mary B. Daly; Capucine Delnatte; Orland Diez; Susan M. Domchek; Cecilia M. Dorfling; Jacqueline Eason; Douglas F. Easton; Ros Eeles; Christoph Engel; D. Gareth Evans; Laurence Faivre; Hanne E. J. Meijers-Heijboer; Jan C. Oosterwijk; Klaartje van Engelen; EMBRACE Collaborators; KConFab Investigators; GEMO Study Collaborators; HEBON Investigators

doi:10.1038/s41416-019-0492-8

Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers

Frank Qian, Matti A. Rookus, Goska Leslie, Harvey A. Risch, Mark H. Greene, Cora M. Aalfs, Muriel A. Adank, Julian Adlard, Bjarni A. Agnarsson, Munaza Ahmed, Kristiina Aittomäki, Irene L. Andrulis, Norbert Arnold, Banu K. Arun, Margreet G. E. M. Ausems, Jacopo Azzollini, Daniel Barrowdale, Julian Barwell, Javier Benitez, Katarzyna BiałkowskaValérie Bonadona, Julika Borde, Ake Borg, Angela R. Bradbury, Joan Brunet, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Jonathan Carter, Jocelyne Chiquette, Wendy K. Chung, Kathleen B. M. Claes, J. Margriet Collée, Marie-Agnès Collonge-Rame, Fergus J. Couch, Mary B. Daly, Capucine Delnatte, Orland Diez, Susan M. Domchek, Cecilia M. Dorfling, Jacqueline Eason, Douglas F. Easton, Ros Eeles, Christoph Engel, D. Gareth Evans, Laurence Faivre, Hanne E. J. Meijers-Heijboer, Jan C. Oosterwijk, Klaartje van Engelen, EMBRACE Collaborators, KConFab Investigators, GEMO Study Collaborators, HEBON Investigators

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

Abstract

Background: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. Methods: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. Results: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94–1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85–1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06–1.48) and HR = 1.59 (95% CI: 1.08–2.33) per 5-kg/m ² increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (P _interaction < 0.05). Conclusion: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.

Original language	English
Pages (from-to)	180-192
Number of pages	13
Journal	British Journal of Cancer
Volume	121
Issue number	2
DOIs	https://doi.org/10.1038/s41416-019-0492-8
Publication status	Published - 16 Jul 2019

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10.1038/s41416-019-0492-8

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Qian, F., Rookus, M. A., Leslie, G., Risch, H. A., Greene, M. H., Aalfs, C. M., Adank, M. A., Adlard, J., Agnarsson, B. A., Ahmed, M., Aittomäki, K., Andrulis, I. L., Arnold, N., Arun, B. K., Ausems, M. G. E. M., Azzollini, J., Barrowdale, D., Barwell, J., Benitez, J., ... HEBON Investigators (2019). Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers. British Journal of Cancer, 121(2), 180-192. https://doi.org/10.1038/s41416-019-0492-8

Qian, Frank ; Rookus, Matti A. ; Leslie, Goska ; Risch, Harvey A. ; Greene, Mark H. ; Aalfs, Cora M. ; Adank, Muriel A. ; Adlard, Julian ; Agnarsson, Bjarni A. ; Ahmed, Munaza ; Aittomäki, Kristiina ; Andrulis, Irene L. ; Arnold, Norbert ; Arun, Banu K. ; Ausems, Margreet G. E. M. ; Azzollini, Jacopo ; Barrowdale, Daniel ; Barwell, Julian ; Benitez, Javier ; Białkowska, Katarzyna ; Bonadona, Valérie ; Borde, Julika ; Borg, Ake ; Bradbury, Angela R. ; Brunet, Joan ; Buys, Saundra S. ; Caldés, Trinidad ; Caligo, Maria A. ; Campbell, Ian ; Carter, Jonathan ; Chiquette, Jocelyne ; Chung, Wendy K. ; Claes, Kathleen B. M. ; Collée, J. Margriet ; Collonge-Rame, Marie-Agnès ; Couch, Fergus J. ; Daly, Mary B. ; Delnatte, Capucine ; Diez, Orland ; Domchek, Susan M. ; Dorfling, Cecilia M. ; Eason, Jacqueline ; Easton, Douglas F. ; Eeles, Ros ; Engel, Christoph ; Evans, D. Gareth ; Faivre, Laurence ; Meijers-Heijboer, Hanne E. J. ; Oosterwijk, Jan C. ; van Engelen, Klaartje ; EMBRACE Collaborators ; KConFab Investigators ; GEMO Study Collaborators ; HEBON Investigators. / Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers. In: British Journal of Cancer. 2019 ; Vol. 121, No. 2. pp. 180-192.

@article{7a09f5edd8d349e9b959c50d21acc2fb,

title = "Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers",

abstract = "Background: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. Methods: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. Results: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94–1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85–1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06–1.48) and HR = 1.59 (95% CI: 1.08–2.33) per 5-kg/m 2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (P interaction < 0.05). Conclusion: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population. ",

author = "Frank Qian and Rookus, {Matti A.} and Goska Leslie and Risch, {Harvey A.} and Greene, {Mark H.} and Aalfs, {Cora M.} and Adank, {Muriel A.} and Julian Adlard and Agnarsson, {Bjarni A.} and Munaza Ahmed and Kristiina Aittom{\"a}ki and Andrulis, {Irene L.} and Norbert Arnold and Arun, {Banu K.} and Ausems, {Margreet G. E. M.} and Jacopo Azzollini and Daniel Barrowdale and Julian Barwell and Javier Benitez and Katarzyna Bia{\l}kowska and Val{\'e}rie Bonadona and Julika Borde and Ake Borg and Bradbury, {Angela R.} and Joan Brunet and Buys, {Saundra S.} and Trinidad Cald{\'e}s and Caligo, {Maria A.} and Ian Campbell and Jonathan Carter and Jocelyne Chiquette and Chung, {Wendy K.} and Claes, {Kathleen B. M.} and Coll{\'e}e, {J. Margriet} and Marie-Agn{\`e}s Collonge-Rame and Couch, {Fergus J.} and Daly, {Mary B.} and Capucine Delnatte and Orland Diez and Domchek, {Susan M.} and Dorfling, {Cecilia M.} and Jacqueline Eason and Easton, {Douglas F.} and Ros Eeles and Christoph Engel and Evans, {D. Gareth} and Laurence Faivre and Meijers-Heijboer, {Hanne E. J.} and Oosterwijk, {Jan C.} and {van Engelen}, Klaartje and {EMBRACE Collaborators} and {KConFab Investigators} and {GEMO Study Collaborators} and {HEBON Investigators}",

note = "Funding Information: We thank all the families and clinicians who contributed to the studies; Sue Healey, in particular taking on the task of mutation classification with the late Olga Sinilnikova; Maggie Angelakos, Judi Maskiell, Gillian Dite, Helen Tsimiklis; members and participants in the New York site of the Breast Cancer Family Registry; members and participants in the Ontario Familial Breast Cancer Registry; Vilius Rudaitis and Laimonas Gri{\v s}kevi{\v c}ius; Drs Janis Eglitis, Anna Krilova and Aivars Stengrevics; Yuan Chun Ding and Linda Steele for their work in participant enrollment and biospecimen and data management; Bent Ejlertsen and Anne-Marie Gerdes for the recruitment and genetic counseling of participants; Alicia Barroso, Rosario Alonso and Guillermo Pita; Manoukian Siranoush, Bernard Peissel, Cristina Zanzottera, Milena Mariani, Daniela Zaffaroni, Bernardo Bonanni, Monica Barile, Irene Feroce, Mariarosaria Calvello, Alessandra Viel, Riccardo Dolcetti, Giuseppe Giannini, Laura Papi, Gabriele Lorenzo Capone, Liliana Varesco, Viviana Gismondi, Maria Grazia Tibiletti, Daniela Furlan, Antonella Savarese, Aline Martayan, Stefania Tommasi, Brunella Pilato; the personnel of the Cogentech Cancer Genetic Test Laboratory, Milan, Italy; Ms. JoEllen Weaver and Dr. Betsy Bove; Marta Santamari{\~n}a, Ana Blanco, Miguel Aguado, Ux{\'i}a Esper{\'o}n and Belinda Rodr{\'i}guez. We thank all participants, clinicians, family doctors, researchers, and technicians for their contributions and commitment to the DKFZ study. Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers (GEMO) study is a study from the National Cancer Genetics Network UNICANCER Genetic Group, France. We wish to pay a tribute to Olga M. Sinilnikova, who with Dominique Stoppa-Lyonnet initiated and coordinated GEMO until she sadly passed away on the 30 June 2014. The team in Lyon (Olga Sinilnikova, M{\'e}lanie L{\'e}on{\'e}, Laure Barjhoux, Carole Verny-Pierre, Sylvie Mazoyer, Francesca Damiola, Val{\'e}rie Sornin) managed the GEMO samples until the biological resource centre was transferred to Paris in December 2015 (Noura Mebirouk, Fabienne Lesueur, Dominique Stoppa-Lyonnet). We want to thank all the GEMO collaborating groups for their contribution to this study: Coordinating Centre, Service de G{\'e}n{\'e}tique, Institut Curie, Paris, France: Muriel Belotti, Oph{\'e}lie Bertrand, Anne-Marie Birot, Bruno Buecher, Sandrine Caputo, Ana{\"i}s Dupr{\'e}, Emmanuelle Fourme, Marion Gauthier-Villars, Lisa Golmard, Claude Houdayer, Marine Le Mentec, Virginie Moncoutier, Antoine de Pauw, Claire Saule, Dominique Stoppa-Lyonnet, and Inserm U900, Institut Curie, Paris, France: Fabienne Lesueur, Noura Mebirouk. Contributing Centres: Unit{\'e} Mixte de G{\'e}n{\'e}tique Constitutionnelle des Cancers Fr{\'e}quents, Hospices Civils de Lyon - Centre L{\'e}on B{\'e}rard, Lyon, France: Nadia Boutry-Kryza, Alain Calender, Sophie Giraud, M{\'e}lanie L{\'e}one. Institut Gustave Roussy, Villejuif, France: Brigitte Bressac-de-Paillerets, Olivier Caron, Marine Guillaud-Bataille. Centre Jean Perrin, Clermont–Ferrand, France: Yves-Jean Bignon, Nancy Uhrhammer. Centre L{\'e}on B{\'e}rard, Lyon, France: Val{\'e}rie Bonadona, Christine Lasset. Centre Fran{\c c}ois Baclesse, Caen, France: Pascaline Berthet, Laurent Castera, Dominique Vaur. Institut Paoli Calmettes, Marseille, France: Violaine Bourdon, Catherine Nogu{\`e}s, Tetsuro Noguchi, Cornel Popovici, Audrey Remenieras, Hagay Sobol. CHU Arnaud-de-Villeneuve, Montpellier, France: Isabelle Coupier, Pascal Pujol. Centre Oscar Lambret, Lille, France: Claude Adenis, Aur{\'e}lie Dumont, Fran{\c c}oise R{\'e}villion. Centre Paul Strauss, Strasbourg, France: Dani{\`e}le Muller. Institut Bergoni{\'e}, Bordeaux, France: Emmanuelle Barouk-Simonet, Fran{\c c}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 Besan{\c c}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 en Brecht Crombez; Ilse Coene and Brecht Crombez; Alicia Tosar and Paula Diaque; Dr. Sofia Khan, Dr. Taru A. Muranen, Dr. Carl Blomqvist, Dr. Irja Erkkil{\"a} and Dr. Virpi Palola; The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centres: Netherlands Cancer Institute (coordinating centre), Amsterdam, NL: M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, M.A. Adank, 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.M. Seynaeve, C.H.M. van Deurzen, I.M. Obdeijn, I.A. Boere; Leiden University Medical Center, NL: C.J. van Asperen, 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, M.J. Koudijs; Amsterdam Medical Center, NL: C.M. Aalfs, H.E.J. Meijers-Heijboer; VU University Medical Center, Amsterdam, NL: K. van Engelen, J.J.P. Gille; Maastricht University Medical Center, NL: E.B. G{\'o}mez-Garcia, M.J. Blok, M. de Boer; University of Groningen, NL: J.C. Oosterwijk, A.H. van der Hout, M.J. Mourits, G.H. de Bock; The Netherlands Comprehensive Cancer Organisation (IKNL): S. Siesling, J.Verloop; The nationwide network and registry of histopathology and cytopathology in The Netherlands (PALGA): A.W. van den Belt-Dusebout. HEBON thanks the study participants and the registration teams of IKNL and PALGA for part of the data collection; 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; the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella; Dr Martine Dumont for sample management and skilful 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 has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contributed to kConFab; the KOBRA Study Group; Csilla Szabo (National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA); Marie Navratilova, Dita Hanouskova and Eva Machackova (Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Brno, Czech Republic); and Michal Zikan, 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 laboratory 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 Comprehensive breast cancer centre team at the Sheba Medical Center; Christina Selkirk; {\AA}ke Borg, H{\aa}kan Olsson, Helena Jernstr{\"o}m, Karin Henriksson, Katja Harbst, Maria Soller, Ulf Kristoffersson; from Gothenburg Sahlgrenska University Hospital: Anna {\"O}fverholm, Margareta Nordling, Per Karlsson, Zakaria Einbeigi; from Stockholm and Karolinska University Hospital: Anna von Wachenfeldt, Annelie Liljegren, Annika Lindblom, Brita Arver, Gisela Barbany Bustinza, Johanna Rantala; 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, Susan Ramus, 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: Funding: CIMBA: The CIMBA data management and data analysis were supported by Cancer Research – UK grants C12292/A20861, C12292/A11174. ACA is a Cancer Research UK Senior Cancer Research Fellow. G.C.T. and A.B.S. 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 (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. BCFR: UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organisations 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.P. J.A. 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 {\textquoteleft}5 × 1000{\textquoteright}). DEMOKRITOS: European Union (European Social Fund – ESF) and Greek national funds through the Operational Program {\textquoteleft}Education and Lifelong Learning{\textquoteright} 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. D.G.E. and F.L. are supported by an NIHR grant to the Biomedical Research Centre, Manchester. 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. R.E. and E.B. are supported by Cancer Research UK Grant C5047/A8385. R.E. 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, R.K.S.). GEMO: Ligue Nationale Contre le Cancer; the Association {\textquoteleft}Le cancer du sein, parlons-en!{\textquoteright} Award, the Canadian Institutes of Health Research for the {\textquoteleft}CIHR Team in Familial Risks of Breast Cancer{\textquoteright} program and the French National Institute of Cancer (INCa grants 2013-1-BCB-01-ICH-1 and SHS-E-SP 18-015). 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 Fore 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, the Finnish Cancer Society and the Sigrid Juselius Foundation. HEBON: the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organisation 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. 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). IHCC: PBZ_KBN_122/P05/2004. ILUH: Icelandic Association {\textquoteleft}Walking for Breast Cancer Research{\textquoteright} 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 {\textquoteleft}5 × 1000{\textquoteright} 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. M.T. is supported by the European Union Seventh Framework Program (2007Y2013)/European Research Council (Grant No. 310018). MODSQUAD: MH CZ - DRO (MMCI, 00209805), MEYS - NPS I - LO1413 to L.F. and by Charles University in Prague project UNCE204024 (to M.Z.). 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), NY. NNPIO: the Russian Foundation for Basic Research (grants 17-54-12007, 17-00-00171 and 18-515-12007). 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, P20CA233307, R01 CA228198, 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. F.Q. was supported by the Alpha Omega Alpha Carolyn L. Cuckein Student Research Fellowship. 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: 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: B.Y.K. 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. D.G.E. is supported by the Manchester NIHR Biomedical Research Centre (IS-BRC-1215-20007). TOR: H.R. is funed by NCI, R01 CA063682. Funding Information: 1Department of Medicine, University of Chicago, Chicago, IL, USA; 2Department of Epidemiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; 3Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; 4Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA; 5Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA; 6Department of Clinical Genetics, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands; 7Family Cancer Clinic, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; 8Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, UK; 9Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland; 10School of Medicine, University of Iceland, Reykjavik, Iceland; 11North East Thames Regional Genetics Service, Great Ormond Street Hospital, London, UK; 12Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland; 13Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada; 14Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; 15Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany; 16Institute of Clinical Molecular Biology, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany; 17Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 18Division Laboratories, Pharmacy and Biomedical Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands; 19Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; 20Leicestershire Clinical Genetics Service, University Hospitals of Leicester NHS Trust, Leicester, UK; 21Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; 22Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain; 23Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland; 24Unit{\'e} de Pr{\'e}vention et d{\textquoteright}Epid{\'e}miologie G{\'e}n{\'e}tique, Centre L{\'e}on B{\'e}rard, Lyon, France; 25Center for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany; 26Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; 27Center for Hereditary Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany; 28Department of Oncology, Lund University and Sk{\aa}ne University Hospital, Lund, Sweden; 29Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; 30Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI (Institut d{\textquoteright}Investigaci{\'o} Biom{\`e}dica de Girona), Catalan Institute of Oncology, CIBERONC, Girona, Spain; 31Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT, USA; 32Medical Oncology Department, Hospital Cl{\'i}nico San Carlos, Instituto de Investigaci{\'o}n Sanitaria San Carlos (IdISSC), Centro Investigaci{\'o}n Biom{\'e}dica en Red de C{\'a}ncer (CIBERONC), Madrid, Spain; 33Section of Molecular Genetics, Dept. of Laboratory Medicine, University Hospital of Pisa, Pisa, Italy; 34Peter MacCallum Cancer Center, Melbourne, Victoria, Australia; 35Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia; 36Department of Gynaecological Oncology, Chris O{\textquoteright}Brien Lifehouse and The University of Sydney, Camperdown, NSW, Australia; 37CRCHU de Qu{\'e}bec-oncologie, Centre des maladies du sein Desch{\^e}nes-Fabia, H{\^o}pital du Saint-Sacrement, Qu{\'e}bec, QC, Canada; 38Departments of Pediatrics and Medicine, Columbia University, New York, NY, USA; 39Centre for Medical Genetics, Ghent University, Gent, Belgium; 40Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands; 41Service de G{\'e}n{\'e}tique, CHU de Besan{\c c}on, Besan{\c c}on, France; 42Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; 43Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA; 44Unit{\'e} d{\textquoteright}Oncog{\'e}n{\'e}tique, ICO-Centre Ren{\'e} Gauducheau, Saint Herblain, France; 45Oncogenetics Group, Clinical and Molecular Genetics Area, Vall d{\textquoteright}Hebron Institute of Oncology (VHIO), University Hospital Vall d{\textquoteright}Hebron, Barcelona, Spain; 46Department of Genetics, University of Pretoria, Arcadia, South Africa; 47Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, UK; 48Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK; 49Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK; 50Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany; 51Division of Evolution and Genomic Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University Funding Information: of Manchester, Manchester Academic Health Science Centre, Manchester, UK; 52Manchester Centre for Genomic Medicine, St Mary{\textquoteright}s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK; 53Unit{\'e} d{\textquoteright}oncog{\'e}n{\'e}tique, Centre de Lutte Contre le Cancer, Centre Georges-Fran{\c c}ois Leclerc, Dijon, France; 54Centre de G{\'e}n{\'e}tique, CHU Dijon, Dijon, France; 55Molecular Diagnostic Unit, Hereditary Cancer Program, ICO-IDIBELL (Bellvitge Biomedical Research Institute, Catalan Institute of Oncology), CIBERONC, Barcelona, Spain;56Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic; 57The Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Ramat Gan, Israel; 58Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel; 59Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research, Jonsson Comprehensive Cancer Centre, UCLA, Los Angeles, CA, USA; 60Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, MA, USA; 61Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University W{\"u}rzburg, W{\"u}rzburg, Germany; 62Department of Pathology and Laboratory Medicine, Kansas University Medical Center, Kansas City, KS, USA; 63Department of Clinical Genetics and GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands; 64Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; 65Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia; 66Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL, USA; 67The University of Chicago Pritzker School of Medicine, Chicago, IL, USA; 68N.N. Petrov Institute of Oncology, St. Petersburg, Russia; 69Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA; 70Clinical Genetics, Guy{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation Trust, London, UK; 71Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland; 72Hematology, oncology and transfusion medicine center, Dept. of Molecular and Regenerative Medicine, Vilnius University Hospital Santariskiu Clinics, Vilnius, Lithuania; 73State Research Institute, Innovative Medicine Center, Vilnius, CA, Lithuania; 74Department of Medicine, Division of Oncology, and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; 75Women{\textquoteright}s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; 76Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; 77D{\'e}partement de G{\'e}n{\'e}tique, CHU de Grenoble, Grenoble, France; 78Genetic Epidemiology of Cancer team, Inserm U900, Paris, France; 79Institut Curie, Paris, France; 80Mines ParisTech, Fontainebleau, France; 81Department of Clinical Genetics, Amsterdam UMC, Location VU University Medical Center, Amsterdam, The Netherlands; 82Department of Gynecology and Obstetrics, Ludwig Maximilian University of Munich, Munich, Germany; 83NRG Oncology, Statistics and Data Management Center, Roswell Park Cancer Institute, Buffalo, NY, USA; 84Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy; 85Service de G{\'e}n{\'e}tique, Institut Curie, Paris, France; 86Clinical Cancer Genomics, City of Hope, Duarte, CA, USA; 87Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA; 88Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland; 89Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; 90Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 91Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 92Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary; 93West Midlands Regional Genetics Service, Birmingham Women{\textquoteright}s Hospital Healthcare NHS Trust, Birmingham, UK; 94Department of Genetics, University Medical Center Groningen, University Groningen, Groningen, The Netherlands; 95Department of Molecular Medicine, University La Sapienza, Rome, Italy; 96Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; 97Genome Diagnostics Program, IFOM - the FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy; 98Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; 99Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy; 100School of Women{\textquoteright}s and Children{\textquoteright}s Health, Faculty of Medicine, University of NSW Sydney, Sydney, NSW, Australia; 101The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW, Australia; 102Clinical Genetics, Karolinska Institutet, Stockholm, Sweden; 103Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel; 104Division of Gynecologic Oncology, NorthShore University HealthSystem, University of Chicago, Evanston, IL, USA; 105Wexner Medical Center, The Ohio State University, Columbus, OH, USA; 106Cancer Genetics and Prevention Program, University of California San Francisco, San Francisco, CA, USA; 107Wessex Clinical Genetics Service, University Hospitals Southampton NHS Trust, Southampton, UK; 108Genomics Center, Centre Hospitalier Universitaire de Qu{\'e}bec – Universit{\'e} Laval, Research Center, Qu{\'e}bec City, QC, Canada; 109Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany; 110Department of Tumour Biology, INSERM U830, Paris, France; 111Universit{\'e} Paris Descartes, Paris, France; 112Department of Genetics, Portuguese Oncology Institute, Porto, Portugal; 113Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal; 114Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA; 115Department of Clinical Genetics, Odense University Hospital, Odence C, Denmark; 116Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montr{\'e}al, QC, Canada; 117Department of Medical Genetics, University of Cambridge, Cambridge, UK; 118Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA; 119Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA; 120Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands; 121Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; 122Department of Medical Oncology, CHU Dupuytren, Limoges, France; 123Oxford Regional Genetics Service, Churchill Hospital, Oxford, UK; 124Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research {\textquoteleft}Demokritos{\textquoteright}, Athens, Greece; 125The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Coordinating Center: The Netherlands Cancer Institute, Amsterdam, The Netherlands; 126Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA; 127Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA; 128Harvard T.H. Chan School of Public Health, Boston, MA, USA; 129Dana-Farber Cancer Institute, Boston, MA, USA and 130Department of Public Health Sciences, University of Chicago, Chicago, IL, USA Publisher Copyright: {\textcopyright} 2019, Cancer Research UK. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",

year = "2019",

month = jul,

day = "16",

doi = "10.1038/s41416-019-0492-8",

language = "English",

volume = "121",

pages = "180--192",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Nature Publishing Group",

number = "2",

}

Qian, F, Rookus, MA, Leslie, G, Risch, HA, Greene, MH, Aalfs, CM, Adank, MA, Adlard, J, Agnarsson, BA, Ahmed, M, Aittomäki, K, Andrulis, IL, Arnold, N, Arun, BK, Ausems, MGEM, Azzollini, J, Barrowdale, D, Barwell, J, Benitez, J, Białkowska, K, Bonadona, V, Borde, J, Borg, A, Bradbury, AR, Brunet, J, Buys, SS, Caldés, T, Caligo, MA, Campbell, I, Carter, J, Chiquette, J, Chung, WK, Claes, KBM, Collée, JM, Collonge-Rame, M-A, Couch, FJ, Daly, MB, Delnatte, C, Diez, O, Domchek, SM, Dorfling, CM, Eason, J, Easton, DF, Eeles, R, Engel, C, Evans, DG, Faivre, L, Meijers-Heijboer, HEJ, Oosterwijk, JC, van Engelen, K, EMBRACE Collaborators, KConFab Investigators, GEMO Study Collaborators & HEBON Investigators 2019, 'Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers', British Journal of Cancer, vol. 121, no. 2, pp. 180-192. https://doi.org/10.1038/s41416-019-0492-8

Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers. / Qian, Frank; Rookus, Matti A.; Leslie, Goska; Risch, Harvey A.; Greene, Mark H.; Aalfs, Cora M.; Adank, Muriel A.; Adlard, Julian; Agnarsson, Bjarni A.; Ahmed, Munaza; Aittomäki, Kristiina; Andrulis, Irene L.; Arnold, Norbert; Arun, Banu K.; Ausems, Margreet G. E. M.; Azzollini, Jacopo; Barrowdale, Daniel; Barwell, Julian; Benitez, Javier; Białkowska, Katarzyna; Bonadona, Valérie; Borde, Julika; Borg, Ake; Bradbury, Angela R.; Brunet, Joan; Buys, Saundra S.; Caldés, Trinidad; Caligo, Maria A.; Campbell, Ian; Carter, Jonathan; Chiquette, Jocelyne; Chung, Wendy K.; Claes, Kathleen B. M.; Collée, J. Margriet; Collonge-Rame, Marie-Agnès; Couch, Fergus J.; Daly, Mary B.; Delnatte, Capucine; Diez, Orland; Domchek, Susan M.; Dorfling, Cecilia M.; Eason, Jacqueline; Easton, Douglas F.; Eeles, Ros; Engel, Christoph; Evans, D. Gareth; Faivre, Laurence; Meijers-Heijboer, Hanne E. J.; Oosterwijk, Jan C.; van Engelen, Klaartje; EMBRACE Collaborators; KConFab Investigators; GEMO Study Collaborators; HEBON Investigators.

In: British Journal of Cancer, Vol. 121, No. 2, 16.07.2019, p. 180-192.

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

TY - JOUR

T1 - Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers

AU - Qian, Frank

AU - Rookus, Matti A.

AU - Leslie, Goska

AU - Risch, Harvey A.

AU - Greene, Mark H.

AU - Aalfs, Cora M.

AU - Adank, Muriel A.

AU - Adlard, Julian

AU - Agnarsson, Bjarni A.

AU - Ahmed, Munaza

AU - Aittomäki, Kristiina

AU - Andrulis, Irene L.

AU - Arnold, Norbert

AU - Arun, Banu K.

AU - Ausems, Margreet G. E. M.

AU - Azzollini, Jacopo

AU - Barrowdale, Daniel

AU - Barwell, Julian

AU - Benitez, Javier

AU - Białkowska, Katarzyna

AU - Bonadona, Valérie

AU - Borde, Julika

AU - Borg, Ake

AU - Bradbury, Angela R.

AU - Brunet, Joan

AU - Buys, Saundra S.

AU - Caldés, Trinidad

AU - Caligo, Maria A.

AU - Campbell, Ian

AU - Carter, Jonathan

AU - Chiquette, Jocelyne

AU - Chung, Wendy K.

AU - Claes, Kathleen B. M.

AU - Collée, J. Margriet

AU - Collonge-Rame, Marie-Agnès

AU - Couch, Fergus J.

AU - Daly, Mary B.

AU - Delnatte, Capucine

AU - Diez, Orland

AU - Domchek, Susan M.

AU - Dorfling, Cecilia M.

AU - Eason, Jacqueline

AU - Easton, Douglas F.

AU - Eeles, Ros

AU - Engel, Christoph

AU - Evans, D. Gareth

AU - Faivre, Laurence

AU - Meijers-Heijboer, Hanne E. J.

AU - Oosterwijk, Jan C.

AU - van Engelen, Klaartje

AU - EMBRACE Collaborators

AU - KConFab Investigators

AU - GEMO Study Collaborators

AU - HEBON Investigators

N1 - Funding Information: We thank all the families and clinicians who contributed to the studies; Sue Healey, in particular taking on the task of mutation classification with the late Olga Sinilnikova; Maggie Angelakos, Judi Maskiell, Gillian Dite, Helen Tsimiklis; members and participants in the New York site of the Breast Cancer Family Registry; members and participants in the Ontario Familial Breast Cancer Registry; Vilius Rudaitis and Laimonas Griškevičius; Drs Janis Eglitis, Anna Krilova and Aivars Stengrevics; Yuan Chun Ding and Linda Steele for their work in participant enrollment and biospecimen and data management; Bent Ejlertsen and Anne-Marie Gerdes for the recruitment and genetic counseling of participants; Alicia Barroso, Rosario Alonso and Guillermo Pita; Manoukian Siranoush, Bernard Peissel, Cristina Zanzottera, Milena Mariani, Daniela Zaffaroni, Bernardo Bonanni, Monica Barile, Irene Feroce, Mariarosaria Calvello, Alessandra Viel, Riccardo Dolcetti, Giuseppe Giannini, Laura Papi, Gabriele Lorenzo Capone, Liliana Varesco, Viviana Gismondi, Maria Grazia Tibiletti, Daniela Furlan, Antonella Savarese, Aline Martayan, Stefania Tommasi, Brunella Pilato; the personnel of the Cogentech Cancer Genetic Test Laboratory, Milan, Italy; Ms. JoEllen Weaver and Dr. Betsy Bove; Marta Santamariña, Ana Blanco, Miguel Aguado, Uxía Esperón and Belinda Rodríguez. We thank all participants, clinicians, family doctors, researchers, and technicians for their contributions and commitment to the DKFZ study. Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers (GEMO) study is a study from the National Cancer Genetics Network UNICANCER Genetic Group, France. We wish to pay a tribute to Olga M. Sinilnikova, who with Dominique Stoppa-Lyonnet initiated and coordinated GEMO until she sadly passed away on the 30 June 2014. The team in Lyon (Olga Sinilnikova, Mélanie Léoné, Laure Barjhoux, Carole Verny-Pierre, Sylvie Mazoyer, Francesca Damiola, Valérie Sornin) managed the GEMO samples until the biological resource centre was transferred to Paris in December 2015 (Noura Mebirouk, Fabienne Lesueur, Dominique Stoppa-Lyonnet). We want to thank all the GEMO collaborating groups for their contribution to this study: Coordinating Centre, Service de Génétique, Institut Curie, Paris, France: Muriel Belotti, Ophélie Bertrand, Anne-Marie Birot, Bruno Buecher, Sandrine Caputo, Anaïs Dupré, Emmanuelle Fourme, Marion Gauthier-Villars, Lisa Golmard, Claude Houdayer, Marine Le Mentec, Virginie Moncoutier, Antoine de Pauw, Claire Saule, Dominique Stoppa-Lyonnet, and Inserm U900, Institut Curie, Paris, France: Fabienne Lesueur, Noura Mebirouk. Contributing Centres: Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon - Centre Léon Bérard, Lyon, France: Nadia Boutry-Kryza, Alain Calender, Sophie Giraud, Mélanie Léone. Institut Gustave Roussy, Villejuif, France: Brigitte Bressac-de-Paillerets, Olivier Caron, Marine Guillaud-Bataille. Centre Jean Perrin, Clermont–Ferrand, France: Yves-Jean Bignon, Nancy Uhrhammer. Centre Léon Bérard, Lyon, France: Valérie Bonadona, Christine Lasset. Centre François Baclesse, Caen, France: Pascaline Berthet, Laurent Castera, Dominique Vaur. Institut Paoli Calmettes, Marseille, France: Violaine Bourdon, Catherine Noguès, Tetsuro Noguchi, Cornel Popovici, Audrey Remenieras, Hagay Sobol. CHU Arnaud-de-Villeneuve, Montpellier, France: Isabelle Coupier, Pascal Pujol. Centre Oscar Lambret, Lille, France: Claude Adenis, Aurélie Dumont, Françoise Révillion. Centre Paul Strauss, Strasbourg, France: Danièle Muller. Institut Bergonié, Bordeaux, France: Emmanuelle Barouk-Simonet, Françoise 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 Besançon, 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 en Brecht Crombez; Ilse Coene and Brecht Crombez; Alicia Tosar and Paula Diaque; Dr. Sofia Khan, Dr. Taru A. Muranen, Dr. Carl Blomqvist, Dr. Irja Erkkilä and Dr. Virpi Palola; The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centres: Netherlands Cancer Institute (coordinating centre), Amsterdam, NL: M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, M.A. Adank, 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.M. Seynaeve, C.H.M. van Deurzen, I.M. Obdeijn, I.A. Boere; Leiden University Medical Center, NL: C.J. van Asperen, 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, M.J. Koudijs; Amsterdam Medical Center, NL: C.M. Aalfs, H.E.J. Meijers-Heijboer; VU University Medical Center, Amsterdam, NL: K. van Engelen, J.J.P. Gille; Maastricht University Medical Center, NL: E.B. Gómez-Garcia, M.J. Blok, M. de Boer; University of Groningen, NL: J.C. Oosterwijk, A.H. van der Hout, M.J. Mourits, G.H. de Bock; The Netherlands Comprehensive Cancer Organisation (IKNL): S. Siesling, J.Verloop; The nationwide network and registry of histopathology and cytopathology in The Netherlands (PALGA): A.W. van den Belt-Dusebout. HEBON thanks the study participants and the registration teams of IKNL and PALGA for part of the data collection; 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; the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella; Dr Martine Dumont for sample management and skilful 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 has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contributed to kConFab; the KOBRA Study Group; Csilla Szabo (National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA); Marie Navratilova, Dita Hanouskova and Eva Machackova (Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Brno, Czech Republic); and Michal Zikan, 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 laboratory 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 Comprehensive breast cancer centre team at the Sheba Medical Center; Christina Selkirk; Åke Borg, Håkan Olsson, Helena Jernström, Karin Henriksson, Katja Harbst, Maria Soller, Ulf Kristoffersson; from Gothenburg Sahlgrenska University Hospital: Anna Öfverholm, Margareta Nordling, Per Karlsson, Zakaria Einbeigi; from Stockholm and Karolinska University Hospital: Anna von Wachenfeldt, Annelie Liljegren, Annika Lindblom, Brita Arver, Gisela Barbany Bustinza, Johanna Rantala; 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, Susan Ramus, 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: Funding: CIMBA: The CIMBA data management and data analysis were supported by Cancer Research – UK grants C12292/A20861, C12292/A11174. ACA is a Cancer Research UK Senior Cancer Research Fellow. G.C.T. and A.B.S. 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 Québec, and The Quebec Breast Cancer Foundation. BCFR: UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organisations 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.P. J.A. 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. D.G.E. and F.L. are supported by an NIHR grant to the Biomedical Research Centre, Manchester. 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. R.E. and E.B. are supported by Cancer Research UK Grant C5047/A8385. R.E. 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, R.K.S.). 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 grants 2013-1-BCB-01-ICH-1 and SHS-E-SP 18-015). 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 Fore 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, the Finnish Cancer Society and the Sigrid Juselius Foundation. HEBON: the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organisation 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. 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). 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. M.T. is supported by the European Union Seventh Framework Program (2007Y2013)/European Research Council (Grant No. 310018). MODSQUAD: MH CZ - DRO (MMCI, 00209805), MEYS - NPS I - LO1413 to L.F. and by Charles University in Prague project UNCE204024 (to M.Z.). 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), NY. NNPIO: the Russian Foundation for Basic Research (grants 17-54-12007, 17-00-00171 and 18-515-12007). 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, P20CA233307, R01 CA228198, 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. F.Q. was supported by the Alpha Omega Alpha Carolyn L. Cuckein Student Research Fellowship. 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: 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: B.Y.K. 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. D.G.E. is supported by the Manchester NIHR Biomedical Research Centre (IS-BRC-1215-20007). TOR: H.R. is funed by NCI, R01 CA063682. Funding Information: 1Department of Medicine, University of Chicago, Chicago, IL, USA; 2Department of Epidemiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; 3Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; 4Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA; 5Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA; 6Department of Clinical Genetics, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands; 7Family Cancer Clinic, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; 8Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, UK; 9Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland; 10School of Medicine, University of Iceland, Reykjavik, Iceland; 11North East Thames Regional Genetics Service, Great Ormond Street Hospital, London, UK; 12Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland; 13Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada; 14Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; 15Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany; 16Institute of Clinical Molecular Biology, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany; 17Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 18Division Laboratories, Pharmacy and Biomedical Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands; 19Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; 20Leicestershire Clinical Genetics Service, University Hospitals of Leicester NHS Trust, Leicester, UK; 21Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; 22Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain; 23Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland; 24Unité de Prévention et d’Epidémiologie Génétique, Centre Léon Bérard, Lyon, France; 25Center for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany; 26Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; 27Center for Hereditary Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany; 28Department of Oncology, Lund University and Skåne University Hospital, Lund, Sweden; 29Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; 30Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI (Institut d’Investigació Biomèdica de Girona), Catalan Institute of Oncology, CIBERONC, Girona, Spain; 31Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT, USA; 32Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; 33Section of Molecular Genetics, Dept. of Laboratory Medicine, University Hospital of Pisa, Pisa, Italy; 34Peter MacCallum Cancer Center, Melbourne, Victoria, Australia; 35Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia; 36Department of Gynaecological Oncology, Chris O’Brien Lifehouse and The University of Sydney, Camperdown, NSW, Australia; 37CRCHU de Québec-oncologie, Centre des maladies du sein Deschênes-Fabia, Hôpital du Saint-Sacrement, Québec, QC, Canada; 38Departments of Pediatrics and Medicine, Columbia University, New York, NY, USA; 39Centre for Medical Genetics, Ghent University, Gent, Belgium; 40Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands; 41Service de Génétique, CHU de Besançon, Besançon, France; 42Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; 43Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA; 44Unité d’Oncogénétique, ICO-Centre René Gauducheau, Saint Herblain, France; 45Oncogenetics Group, Clinical and Molecular Genetics Area, Vall d’Hebron Institute of Oncology (VHIO), University Hospital Vall d’Hebron, Barcelona, Spain; 46Department of Genetics, University of Pretoria, Arcadia, South Africa; 47Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, UK; 48Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK; 49Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK; 50Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany; 51Division of Evolution and Genomic Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University Funding Information: of Manchester, Manchester Academic Health Science Centre, Manchester, UK; 52Manchester Centre for Genomic Medicine, St Mary’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK; 53Unité d’oncogénétique, Centre de Lutte Contre le Cancer, Centre Georges-François Leclerc, Dijon, France; 54Centre de Génétique, CHU Dijon, Dijon, France; 55Molecular Diagnostic Unit, Hereditary Cancer Program, ICO-IDIBELL (Bellvitge Biomedical Research Institute, Catalan Institute of Oncology), CIBERONC, Barcelona, Spain;56Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic; 57The Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Ramat Gan, Israel; 58Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel; 59Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research, Jonsson Comprehensive Cancer Centre, UCLA, Los Angeles, CA, USA; 60Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, MA, USA; 61Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University Würzburg, Würzburg, Germany; 62Department of Pathology and Laboratory Medicine, Kansas University Medical Center, Kansas City, KS, USA; 63Department of Clinical Genetics and GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands; 64Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; 65Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia; 66Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL, USA; 67The University of Chicago Pritzker School of Medicine, Chicago, IL, USA; 68N.N. Petrov Institute of Oncology, St. Petersburg, Russia; 69Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA; 70Clinical Genetics, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 71Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland; 72Hematology, oncology and transfusion medicine center, Dept. of Molecular and Regenerative Medicine, Vilnius University Hospital Santariskiu Clinics, Vilnius, Lithuania; 73State Research Institute, Innovative Medicine Center, Vilnius, CA, Lithuania; 74Department of Medicine, Division of Oncology, and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; 75Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; 76Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; 77Département de Génétique, CHU de Grenoble, Grenoble, France; 78Genetic Epidemiology of Cancer team, Inserm U900, Paris, France; 79Institut Curie, Paris, France; 80Mines ParisTech, Fontainebleau, France; 81Department of Clinical Genetics, Amsterdam UMC, Location VU University Medical Center, Amsterdam, The Netherlands; 82Department of Gynecology and Obstetrics, Ludwig Maximilian University of Munich, Munich, Germany; 83NRG Oncology, Statistics and Data Management Center, Roswell Park Cancer Institute, Buffalo, NY, USA; 84Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy; 85Service de Génétique, Institut Curie, Paris, France; 86Clinical Cancer Genomics, City of Hope, Duarte, CA, USA; 87Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA; 88Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland; 89Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; 90Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 91Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 92Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary; 93West Midlands Regional Genetics Service, Birmingham Women’s Hospital Healthcare NHS Trust, Birmingham, UK; 94Department of Genetics, University Medical Center Groningen, University Groningen, Groningen, The Netherlands; 95Department of Molecular Medicine, University La Sapienza, Rome, Italy; 96Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; 97Genome Diagnostics Program, IFOM - the FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy; 98Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; 99Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy; 100School of Women’s and Children’s Health, Faculty of Medicine, University of NSW Sydney, Sydney, NSW, Australia; 101The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW, Australia; 102Clinical Genetics, Karolinska Institutet, Stockholm, Sweden; 103Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel; 104Division of Gynecologic Oncology, NorthShore University HealthSystem, University of Chicago, Evanston, IL, USA; 105Wexner Medical Center, The Ohio State University, Columbus, OH, USA; 106Cancer Genetics and Prevention Program, University of California San Francisco, San Francisco, CA, USA; 107Wessex Clinical Genetics Service, University Hospitals Southampton NHS Trust, Southampton, UK; 108Genomics Center, Centre Hospitalier Universitaire de Québec – Université Laval, Research Center, Québec City, QC, Canada; 109Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany; 110Department of Tumour Biology, INSERM U830, Paris, France; 111Université Paris Descartes, Paris, France; 112Department of Genetics, Portuguese Oncology Institute, Porto, Portugal; 113Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal; 114Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA; 115Department of Clinical Genetics, Odense University Hospital, Odence C, Denmark; 116Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, QC, Canada; 117Department of Medical Genetics, University of Cambridge, Cambridge, UK; 118Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA; 119Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA; 120Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands; 121Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; 122Department of Medical Oncology, CHU Dupuytren, Limoges, France; 123Oxford Regional Genetics Service, Churchill Hospital, Oxford, UK; 124Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research ‘Demokritos’, Athens, Greece; 125The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Coordinating Center: The Netherlands Cancer Institute, Amsterdam, The Netherlands; 126Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA; 127Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA; 128Harvard T.H. Chan School of Public Health, Boston, MA, USA; 129Dana-Farber Cancer Institute, Boston, MA, USA and 130Department of Public Health Sciences, University of Chicago, Chicago, IL, USA Publisher Copyright: © 2019, Cancer Research UK. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2019/7/16

Y1 - 2019/7/16

N2 - Background: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. Methods: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. Results: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94–1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85–1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06–1.48) and HR = 1.59 (95% CI: 1.08–2.33) per 5-kg/m 2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (P interaction < 0.05). Conclusion: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.

AB - Background: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. Methods: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. Results: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94–1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85–1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06–1.48) and HR = 1.59 (95% CI: 1.08–2.33) per 5-kg/m 2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (P interaction < 0.05). Conclusion: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.

UR - http://www.scopus.com/inward/record.url?scp=85067846442&partnerID=8YFLogxK

U2 - 10.1038/s41416-019-0492-8

DO - 10.1038/s41416-019-0492-8

M3 - Article

C2 - 31213659

VL - 121

SP - 180

EP - 192

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

IS - 2

ER -

Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers

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