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/m2 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.

Biomedical Sciences Institute University of Porto Porto Portugal

Breast Cancer Research Unit Cancer Research Institute University Malaya Medical Centre Kuala Lumpur Malaysia

Cancer Genetics and Prevention Program University of California San Francisco San Francisco CA

Cancer Research Malaysia Subang Jaya Selangor Malaysia

Cancer Risk and Prevention Clinic Dana Farber Cancer Institute Boston MA

Center for Clinical Cancer Genetics The University of Chicago Chicago IL

Center for Genomic Medicine Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Center for Medical Genetics NorthShore University HealthSystem Evanston IL

Centers for Hereditary Breast and Ovarian Cancer Integrated Oncology and Molecular Medicine University Hospital of Cologne Cologne Germany Molecular Genetics of Breast Cancer German Cancer Research Center Heidelberg Germany

Centre for Cancer Genetic Epidemiology Department of Oncology University of Cambridge Cambridge UK

Centre for Cancer Research and Cell Biology Queens University Belfast Belfast UK

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Melbourne Victoria Australia

Centre for Medical Genetics Ghent University Ghent Belgium

Centro de Investigación en Red de Enfermedades Raras Valencia Spain Department of Obstetrics and Gynecology Medical University of Vienna Vienna Austria

City of Hope Clinical Cancer Genetics Community Research Network Duarte CA

Clinical Cancer Genetics City of Hope Duarte CA

Clinical Genetics Branch Division of Cancer Epidemiology and Genetics National Cancer Institute Rockville MD

Clinical Genetics Guy's and St Thomas' NHS Foundation Trust London UK

Clinical Genetics Karolinska Institutet Stockholm Sweden

Clinical Genetics Research Laboratory Department of Cancer Biology and Genetics Memorial Sloan Kettering Cancer Center New York NY

Clinical Genetics Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY

Dana Farber Cancer Institute Harvard Medical School Boston MA

Department of Breast Medical Oncology University of Texas MD Anderson Cancer Center Houston TX

Department of Cancer Biology and Genetics Comprehensive Cancer Center The Ohio State University Columbus OH

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Cancer Epidemiology Moffitt Cancer Center Tampa FL

Department of Clinical Genetics Academic Medical Center Amsterdam the Netherlands

Department of Clinical Genetics and GROW School for Oncology and Developmental Biology Maastricht University Medical Center Maastricht the Netherlands

Department of Clinical Genetics Erasmus University Medical Center Rotterdam the Netherlands

Department of Clinical Genetics Fox Chase Cancer Center Philadelphia PA

Department of Clinical Genetics Helsinki University Hospital University of Helsinki Helsinki Finland

Department of Clinical Genetics Leiden University Medical Center Leiden the Netherlands

Department of Clinical Genetics Odense University Hospital Odense C Denmark

Department of Clinical Genetics South Glasgow University Hospitals Glasgow UK

Department of Clinical Genetics VU University Medical Center Amsterdam the Netherlands

Department of Dermatology Huntsman Cancer Institute University of Utah School of Medicine Salt Lake City UT

Department of Epidemiology and Biostatistics School of Public Health Peking University Health Science Center Beijing China

Department of Epidemiology Mailman School of Public Health Columbia University New York NY

Department of Epidemiology Netherlands Cancer Institute Amsterdam the Netherlands

Department of Genetics and Computational Biology QIMR Berghofer Medical Research Institute Brisbane Queensland Australia

Department of Genetics and Pathology Pomeranian Medical University Szczecin Poland

Department of Genetics Portuguese Oncology Institute Porto Portugal

Department of Genetics University Medical Center Groningen University of Groningen Groningen the Netherlands

Department of Genetics University of Pretoria Arcadia South Africa

Department of Gynaecology and Obstetrics University of Ulm Ulm Germany

Department of Gynecology and Obstetrics Technical University of Dresden Dresden Germany

Department of Gynecology and Obstetrics University Hospital Düsseldorf Heinrich Heine University Düsseldorf Düsseldorf Germany

Department of Human Genetics Radboud University Medical Center Nijmegen the Netherlands

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN

Department of Medical Genetics Addenbrooke's Hospital Cambridge UK

Department of Medical Genetics University Medical Center Utrecht the Netherlands

Department of Medical Oncology Beth Israel Deaconess Medical Center Boston MA

Department of Medicine Abramson Cancer Center Perelman School of Medicine at the University of Pennsylvania Philadelphia PA

Department of Medicine Huntsman Cancer Institute at the University of Utah Salt Lake City UT

Department of Medicine The University of Chicago Chicago IL

Department of Molecular Genetics National Institute of Oncology Budapest Hungary

Department of Molecular Genetics University of Toronto Toronto ON Canada

Department of Molecular Medicine University La Sapienza Rome Italy

Department of Obstetrics and Gynecology and Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Department of Obstetrics and Gynecology Helsinki University Hospital University of Helsinki Helsinki Finland

Department of Oncology Lund University and Skåne University Hospital Lund Sweden

Department of Pathology and Laboratory Medicine Kansas University Medical Center Kansas City KS

Department of Pathology National Institute of Oncology Budapest Hungary

Department of Population Sciences Beckman Research Institute of City of Hope Duarte CA

Department of Public Health and Primary Care Centre for Cancer Genetic Epidemiology University of Cambridge Cambridge UK

Department of Public Health Sciences The University of Chicago Chicago IL

Department of Surgery Daerim Saint Mary's Hospital Seoul Korea

Department of Surgery Hong Kong Sanatorium and Hospital Happy Valley Hong Kong

Department of Surgery Seoul National University Bundang Hospital Seongnam Korea

Department of Surgery Soonchunhyang University College of Medicine and Soonchunhyang University Hospital Seoul Korea

Department of Surgery Soonchunhyang University Hospital Bucheon Bucheon Korea

Department of Surgery The University of Hong Kong Pok Fu Lam Hong Kong

Department of Surgery Ulsan University College of Medicine and Asan Medical Center Seoul Korea

Department of Tumour Biology Institut Curie INSERM U830 Paris France

Department of Urology Medical University of Vienna Vienna Austria

Departments of Pediatrics and Medicine Columbia University New York NY

Departments of Preventive Medicine and Biomedical Sciences and Cancer Research Institute Seoul National University Seoul Korea

Division of Evolution and Genomic Sciences Genomic Medicine Manchester Academic Health Sciences Centre University of Manchester Central Manchester University Hospitals NHS Foundation Trust Manchester UK

Division of Gastroenterology Department of Hepatology and Nutrition Children's Hospital of Philadelphia Philadelphia PA

Division of Gynaecology and Obstetrics Technische Universität München Munich Germany

Division of Gynecologic Oncology NorthShore University HealthSystem University of Chicago Evanston IL

Family Cancer Clinic Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam the Netherlands

Fred A Litwin Center for Cancer Genetics Lunenfeld Tanenbaum Research Institute of Mount Sinai Hospital Toronto ON Canada

Genetic Counseling Unit Hereditary Cancer Program IDIBGI Catalan Institute of Oncology CIBERONC Girona Spain

Genetic Epidemiology of Cancer team Institut Curie Paris France

Genomics Center Centre Hospitalier Universitaire de Québec Research Center Laval University Québec City QC Canada

Harvard T H Chan School of Public Health Boston MA

Hereditary Cancer Centre Prince of Wales Hospital Sydney New South Wales Australia

Hong Kong Hereditary Breast Cancer Family Registry Happy Valley Hong Kong

Human Cancer Genetics Program Spanish National Cancer Research Centre Madrid Spain

IFOM The FIRC Institute of Molecular Oncology Milan Italy

Immunology and Molecular Oncology Unit Veneto Institute of Oncology IOV IRCCS Padua Italy

Institute for Medical Informatics Statistics and Epidemiology University of Leipzig Leipzig Germany

Institute of Genetic Medicine Centre for Life Newcastle Upon Tyne Hospitals NHS Trust Newcastle upon Tyne UK

Institute of Human Genetics University Hospital Heidelberg Heidelberg Germany

Laboratoire de génétique médicale Nancy Université Centre Hospitalier Régional et Universitaire Vandoeuvre les Nancy France

Leicestershire Clinical Genetics Service University Hospitals of Leicester NHS Trust Leicester UK

LIFE Leipzig Research Centre for Civilization Diseases University of Leipzig Leipzig Germany

Lombardi Comprehensive Cancer Center Georgetown University Washington DC

Mines ParisTech Fontainebleau France

Molecular Diagnostic Unit Hereditary Cancer Program ICO IDIBELL CIBERONC Barcelona Spain

Molecular Diagnostics Laboratory INRASTES National Centre for Scientific Research 'Demokritos' Athens Greece

Molecular Oncology Laboratory Hospital Clinico San Carlos IdISSC CIBERONC Madrid Spain

N N Petrov Institute of Oncology St Petersburg Russia

NRG Oncology Statistics and Data Management Center Roswell Park Cancer Institute Buffalo NY

Ocogenetics Team The Institute of Cancer Research and Royal Marsden NHS Foundation Trust London UK

Oncogenetics Group Clinical and Molecular Genetics Area Vall d'Hebron Institute of Oncology ; Clinical Genetics Department St Michael's Hospital Bristol UK

Oncogénétique Institut Bergonié Bordeaux France

Peter MacCallum Cancer Center Melbourne Victoria Australia

Program in Cancer Genetics Departments of Human Genetics and Oncology McGill University Montréal QC Canada

PSL University Paris France

Sackler Faculty of Medicine Tel Aviv University Ramat Aviv Israel

School of Medicine University of Iceland Reykjavik Iceland

School of Medicine University of New South Wales Sydney New South Wales Australia

School of Women's and Children's Health University of New South Wales Sydney New South Wales Australia

Schools of Medicine and Public Health Division of Cancer Prevention and Control Research Jonsson Comprehensive Cancer Center University of California Los Angeles CA

Section of Genetic Oncology Department of Laboratory Medicine University and University Hospital of Pisa Pisa Italy

Service de Génétique Institut Curie Paris France

Sir Peter MacCallum Department of Oncology The University of Melbourne Melbourne Victoria Australia

The Kinghorn Cancer Centre Garvan Institute of Medical Research Sydney New South Wales Australia

The Ohio State University Columbus Cancer Council Columbus OH

The Susanne Levy Gertner Oncogenetics Unit Chaim Sheba Medical Center Ramat Gan Israel

The University of Chicago Pritzker School of Medicine Chicago IL

U900 INSERM Paris France

Unit of Medical Genetics Department of Medical Oncology and Hematology Fondazione IRCCS Milan Italy

Unit of Molecular Bases of Genetic Risk and Genetic Testing Department of Research Fondazione IRCCS Milan Italy

Unité d'Oncogénétique CHU Arnaud de Villeneuve Montpellier France

Unité de Prévention et d'Epidémiologie Génétique Centre Léon Bérard Lyon France

Unité de recherche en santé des populations Centre des maladies du sein Deschênes Fabia Hôpital du Saint Sacrement Québec QC Canada

Université Paris Descartes Paris France

West Midlands Regional Genetics Service Birmingham Women's Hospital Healthcare NHS Trust Birmingham UK

Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute Cedars Sinai Medical Center Los Angeles CA

Yorkshire Regional Genetics Service Chapel Allerton Hospital Leeds UK

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Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium

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