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

Qian F 1 , Wang S 2 , Mitchell J 3 , McGuffog L 4 , Barrowdale D 4 , Leslie G 4 Show all authors , Oosterwijk JC 5 , Chung WK 6 , Evans DG 7 , Engel C 8 , Kast K 9 , Aalfs CM 10 , Adank MA 11 , Adlard J 12 , Agnarsson BA 13 , Aittomäki K 14 , Alducci E 15 , Andrulis IL 16 , Arun BK 17 , Ausems MGEM 18 , Azzollini J 19 , Barouk-Simonet E 20 , Barwell J 21 , Belotti M 22 , Benitez J 23 , Berger A 24 , Borg A 25 , Bradbury AR 26 , Brunet J 22 , Buys SS 27 , Caldes T 28 , Caligo MA 29 , Campbell I 30 , Caputo SM 21 , Chiquette J 31 , Claes KBM 32 , Margriet Collée J 33 , Couch FJ 34 , Coupier I 35 , Daly MB 36 , Davidson R 37 , Diez O 38 , Domchek SM 26 , Donaldson A 39 , Dorfling CM 40 , Eeles R 41 , Feliubadaló L 42 , Foretova L 43 , Fowler J 44 , Friedman E 45 , Frost D 4 , Ganz PA 23 , Garber J 25 , Garcia-Barberan V 28 , Glendon G 16 , Godwin AK 46 , Gómez Garcia EB 47 , Gronwald J 47 , Hahnen E 48 , Hamann U , Henderson A 49 , Hendricks CB 50 , Hopper JL 42 , Hulick PJ 51 , Imyanitov EN 38 , Isaacs C 52 , Izatt L 53 , Izquierdo Á 54 , Jakubowska A 47 , Kaczmarek K 47 , Kang E 55 , Karlan BY 56 , Kets CM 57 , Kim SW 58 , Kim Z 59 , Kwong A 60 , Laitman Y 45 , Lasset C 61 , Hyuk Lee M 62 , Won Lee J 63 , Lee J 47 , Lester J 47 , Lesueur F 64 , Loud JT 65 , Lubinski J 47 , Mebirouk N 64 , Meijers-Heijboer HEJ 66 , Meindl A 67 , Miller A 67 , Montagna M 68 , Mooij TM 69 , Morrison PJ 70 , Mouret-Fourme E 22 , Nathanson KL , Neuhausen SL 71 , Nevanlinna H 72 , Niederacher D 73 , Nielsen FC 74 , Nussbaum RL 75 , Offit K 76 , Olah E 77 , Ong KR 78 , Ottini L 79 , Park SK 80 , Peterlongo P 81 , Pfeiler G 82 , Phelan CM 83 , Poppe B 32 , Pradhan N 76 , Radice P 84 , Ramus SJ 85 , Rantala J 86 , Robson M 87 , Rodriguez GC 88 , Schmutzler RK 48 , Hutten Selkirk CG 51 , Shah PD 26 , Simard J 89 , Singer CF 90 , Sokolowska J 91 , Stoppa-Lyonnet D 92 , Sutter C 93 , Yen Tan Y 94 , Teixeira RM 95 , Teo SH 96 , Terry MB 97 , Thomassen M 98 , Tischkowitz M 99 , Toland AE 100 , Tucker KM 101 , Tung N 102 , van Asperen CJ 103 , van Engelen K 10 , van Rensburg EJ 40 , Wang-Gohrke S 104 , Wappenschmidt B 48 , Weitzel JN 105 , Yannoukakos D 106 , GEMO Study Collaborators , HEBON , EMBRACE , Greene MH 65 , Rookus MA 69 , Easton DF 4 , Chenevix-Trench G 107 , Antoniou AC 4 , Goldgar DE 108 , Olopade OI 1 , Rebbeck TR 109 , Huo D 1

Affiliations 

  • 1 Department of Medicine, The University of Chicago, Chicago, IL
  • 2 Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL
  • 3 Division of Gastroenterology, Department of Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA
  • 4 Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK
  • 5 Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
  • 6 Departments of Pediatrics and Medicine, Columbia University, New York, NY
  • 7 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
  • 8 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
  • 9 Department of Gynecology and Obstetrics, Technical University of Dresden, Dresden, Germany
  • 10 Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands
  • 11 Family Cancer Clinic, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
  • 12 Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, UK
  • 13 Department of Pathology, National Institute of Oncology, Budapest, Hungary
  • 14 Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  • 15 Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy
  • 16 Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada
  • 17 Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX
  • 18 Department of Medical Genetics, University Medical Center, Utrecht, the Netherlands
  • 19 Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Milan, Italy
  • 20 Oncogénétique, Institut Bergonié, Bordeaux, France
  • 21 Leicestershire Clinical Genetics Service, University Hospitals of Leicester NHS Trust, Leicester, UK
  • 22 Service de Génétique, Institut Curie, Paris, France
  • 23 Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research, Jonsson Comprehensive Cancer Center, University of California Los Angeles, CA
  • 24 Department of Oncology, Lund University and Skåne University Hospital, Lund, Sweden
  • 25 Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, MA
  • 26 Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
  • 27 Department of Medicine, Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT
  • 28 Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, CIBERONC, Madrid, Spain
  • 29 Section of Genetic Oncology, Department of Laboratory Medicine, University and University Hospital of Pisa, Pisa, Italy
  • 30 Peter MacCallum Cancer Center, Melbourne, Victoria, Australia
  • 31 Unité de recherche en santé des populations, Centre des maladies du sein Deschênes-Fabia, Hôpital du Saint-Sacrement, Québec, QC, Canada
  • 32 Centre for Medical Genetics, Ghent University, Ghent, Belgium
  • 33 Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands
  • 34 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
  • 35 Unité d'Oncogénétique, CHU Arnaud de Villeneuve, Montpellier, France
  • 36 Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA
  • 37 Department of Clinical Genetics, South Glasgow University Hospitals, Glasgow, UK
  • 38 N.N. Petrov Institute of Oncology, St. Petersburg, Russia
  • 39 Oncogenetics Group, Clinical and Molecular Genetics Area, Vall d'Hebron Institute of Oncology (VHIO), University Hospital, Vall d'Hebron, Barcelona, Spain (OD); Clinical Genetics Department, St Michael's Hospital, Bristol, UK
  • 40 Department of Genetics, University of Pretoria, Arcadia, South Africa
  • 41 Ocogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK
  • 42 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
  • 43 Molecular Diagnostic Unit, Hereditary Cancer Program, ICO-IDIBELL (Catalan Institute of Oncology, Bellvitge Biomedical Research Institute), CIBERONC, Barcelona, Spain
  • 44 The Ohio State University, Columbus Cancer Council, Columbus, OH
  • 45 The Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Ramat Gan, Israel
  • 46 Department of Pathology and Laboratory Medicine, Kansas University Medical Center, Kansas City, KS
  • 47 Department of Clinical Genetics and GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands
  • 48 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 (DKFZ), Heidelberg, Germany
  • 49 Institute of Genetic Medicine, Centre for Life, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK
  • 50 City of Hope Clinical Cancer Genetics Community Research Network, Duarte, CA
  • 51 Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL
  • 52 Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC (CI)
  • 53 Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK
  • 54 Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI (Institut d'Investigació Biomèdica de Girona), Catalan Institute of Oncology, CIBERONC, Girona, Spain
  • 55 Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea
  • 56 Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA
  • 57 Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
  • 58 Department of Surgery, Daerim Saint Mary's Hospital, Seoul, Korea
  • 59 Department of Surgery, Soonchunhyang University Hospital Bucheon, Bucheon, Korea
  • 60 Hong Kong Hereditary Breast Cancer Family Registry, Happy Valley, Hong Kong
  • 61 Unité de Prévention et d'Epidémiologie Génétique, Centre Léon Bérard, Lyon, France
  • 62 Department of Surgery, Soonchunhyang University College of Medicine and Soonchunhyang University Hospital, Seoul, Korea
  • 63 Department of Surgery, Ulsan University College of Medicine and Asan Medical Center, Seoul, Korea
  • 64 Genetic Epidemiology of Cancer team, Institut Curie, Paris, France
  • 65 Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD
  • 66 Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands
  • 67 Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany
  • 68 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 69 Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands
  • 70 Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, UK
  • 71 Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA
  • 72 Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  • 73 Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
  • 74 Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  • 75 Cancer Genetics and Prevention Program, University of California San Francisco, San Francisco, CA
  • 76 Clinical Genetics Research Laboratory, Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY
  • 77 Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary
  • 78 West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Birmingham, UK
  • 79 Department of Molecular Medicine, University La Sapienza, Rome, Italy
  • 80 Departments of Preventive Medicine and Biomedical Sciences, and Cancer Research Institute, Seoul National University, Seoul, Korea
  • 81 IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy
  • 82 Department of Urology, Medical University of Vienna, Vienna, Austria
  • 83 Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL
  • 84 Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Milan, Italy
  • 85 School of Women's and Children's Health, University of New South Wales Sydney, New South Wales, Australia
  • 86 Clinical Genetics, Karolinska Institutet, Stockholm, Sweden
  • 87 Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY
  • 88 Division of Gynecologic Oncology, NorthShore University HealthSystem, University of Chicago, Evanston, IL
  • 89 Laboratoire de génétique médicale, Nancy Université, Centre Hospitalier Régional et Universitaire, Vandoeuvre-les-Nancy, France
  • 90 Department of Obstetrics and Gynecology and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
  • 91 Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, QC, Canada
  • 92 Department of Tumour Biology, Institut Curie, INSERM U830, Paris, France
  • 93 Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany
  • 94 Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain, Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
  • 95 Department of Genetics, Portuguese Oncology Institute, Porto, Portugal
  • 96 Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia
  • 97 Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY
  • 98 Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark
  • 99 Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, QC, Canada
  • 100 Department of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH
  • 101 School of Medicine, University of New South Wales, Sydney, New South Wales, Australia
  • 102 Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA
  • 103 Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands
  • 104 Department of Gynaecology and Obstetrics, University of Ulm, Ulm, Germany
  • 105 Clinical Cancer Genetics, City of Hope, Duarte, CA
  • 106 Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens, Greece
  • 107 Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  • 108 Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT
  • 109 Harvard T.H. Chan School of Public Health, Boston, MA
J Natl Cancer Inst, 2019 Apr 01;111(4):350-364.
PMID: 30312457 DOI: 10.1093/jnci/djy132

Abstract

BACKGROUND: BRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 mutation carriers remains unclear.

METHODS: We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants. We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided.

RESULTS: Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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