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BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer

Shimelis H 1 , Mesman RLS 2 , Von Nicolai C 3 , Ehlen A 3 , Guidugli L 4 , Martin C 5 Show all authors , Calléja FMGR 2 , Meeks H 6 , Hallberg E 7 , Hinton J 7 , Lilyquist J 7 , Hu C 1 , Aalfs CM 8 , Aittomäki K 9 , Andrulis I 10 , Anton-Culver H 11 , Arndt V 12 , Beckmann MW 13 , Benitez J 14 , Bogdanova NV 15 , Bojesen SE 16 , Bolla MK 17 , Borresen-Dale AL 18 , Brauch H 19 , Brennan P 20 , Brenner H 12 , Broeks A 21 , Brouwers B 22 , Brüning T 23 , Burwinkel B 24 , Chang-Claude J 25 , Chenevix-Trench G , Cheng CY 26 , Choi JY 27 , Collée JM 28 , Cox A 29 , Cross SS 30 , Czene K 31 , Darabi H 31 , Dennis J 17 , Dörk T 32 , Dos-Santos-Silva I 33 , Dunning AM 34 , Fasching PA 13 , Figueroa J 35 , Flyger H 36 , García-Closas M 37 , Giles GG 38 , Glendon G 10 , Guénel P 39 , Haiman CA 40 , Hall P 31 , Hamann U 41 , Hartman M 42 , Hogervorst FB 21 , Hollestelle A 43 , Hopper JL 44 , Ito H 45 , Jakubowska A 46 , Kang D 27 , Kosma VM 47 , Kristensen V , Lai KN 48 , Lambrechts D 49 , Marchand LL 50 , Li J 31 , Lindblom A 51 , Lophatananon A 52 , Lubinski J 46 , Machackova E 53 , Mannermaa A 47 , Margolin S 54 , Marme F 24 , Matsuo K 55 , Miao H 42 , Michailidou K 17 , Milne RL 38 , Muir K 52 , Neuhausen SL 56 , Nevanlinna H 57 , Olson JE 7 , Olswold C 7 , Oosterwijk JJC 58 , Osorio A 14 , Peterlongo P 59 , Peto J 33 , Pharoah PDP 17 , Pylkäs K 60 , Radice P 61 , Rashid MU 41 , Rhenius V 34 , Rudolph A 25 , Sangrajrang S 62 , Sawyer EJ 63 , Schmidt MK 21 , Schoemaker MJ 64 , Seynaeve C 43 , Shah M 34 , Shen CY 65 , Shrubsole M 66 , Shu XO 66 , Slager S 7 , Southey MC 67 , Stram DO 40 , Swerdlow A 64 , Teo SH 48 , Tomlinson I 68 , Torres D 41 , Truong T 39 , van Asperen CJ 8 , van der Kolk LE 21 , Wang Q 17 , Winqvist R 60 , Wu AH 40 , Yu JC 69 , Zheng W 66 , Zheng Y 70 , Leary J 71 , Walker L 72 , Foretova L 53 , Fostira F 73 , Claes KBM 74 , Varesco L 75 , Moghadasi S 8 , Easton DF 17 , Spurdle A 76 , Devilee P 2 , Vrieling H 2 , Monteiro ANA 77 , Goldgar DE 78 , Carreira A 3 , Vreeswijk MPG 2 , Couch FJ 79 , for kConFab/AOCS Investigators , for NBCS Collaborators

Affiliations 

  • 1 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
  • 2 Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
  • 3 Genotoxic Stress and Cancer, Institut Curie, Orsay, France
  • 4 Department of Human Genetics, University of Chicago, Chicago, Illinois
  • 5 Research Center, Institute Curie, Orsay, France
  • 6 Cancer Control and Population Sciences, University of Utah, Salt Lake City, Utah
  • 7 Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
  • 8 Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands
  • 9 Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  • 10 Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada
  • 11 Department of Epidemiology, University of California Irvine, Irvine, California
  • 12 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 13 Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
  • 14 Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain
  • 15 Department of Radiation Oncology, Hannover Medical School, Hannover, Germany
  • 16 Copenhagen General Population Study, Herlevand Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  • 17 Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
  • 18 Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway
  • 19 Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany
  • 20 International Agency for Research on Cancer, Lyon, France
  • 21 Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
  • 22 Laboratory of Experimental Oncology, Department of Oncology, University Hospitals Leuven, Leuven, Belgium
  • 23 Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum, Bochum, Germany
  • 24 Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany
  • 25 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 26 Singapore Eye Research Institute, National University of Singapore, Singapore, Singapore
  • 27 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
  • 28 Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands
  • 29 Sheffield Cancer Research, Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom
  • 30 Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, United Kingdom
  • 31 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  • 32 Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
  • 33 Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom
  • 34 Department of Oncology, University of Cambridge, Cambridge, United Kingdom
  • 35 Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh, United Kingdom
  • 36 Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  • 37 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
  • 38 Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia
  • 39 Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France
  • 40 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
  • 41 Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 42 Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
  • 43 Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
  • 44 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia
  • 45 Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
  • 46 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 47 Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland
  • 48 Cancer Research Initiatives Foundation, Subang Jaya, Selangor, Malaysia
  • 49 Vesalius Research Center, Leuven, Belgium
  • 50 University of Hawaii Cancer Center, Honolulu, Hawaii
  • 51 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
  • 52 Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, United Kingdom
  • 53 Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic
  • 54 Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden
  • 55 Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
  • 56 Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California
  • 57 Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  • 58 Department of Genetics, University of Groningen, Groningen, the Netherlands
  • 59 IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy
  • 60 Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland
  • 61 Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Milan, Italy
  • 62 National Cancer Institute, Bangkok, Thailand
  • 63 Research Oncology, Guy's Hospital, King's College London, London, United Kingdom
  • 64 Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom
  • 65 School of Public Health, China Medical University, Taichung, Taiwan
  • 66 Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
  • 67 Department of Pathology, The University of Melbourne, Melbourne, Australia
  • 68 Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
  • 69 Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
  • 70 Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China
  • 71 Westmead Millenium Institute for Medical Research, University of Sydney, Sydney, Australia
  • 72 Department of Pathology, University of Otago, Christchurch, New Zealand
  • 73 Molecular Diagnostics Laboratory, Institute of Radioisotopes and Radiodiagnostic Products (IRRP), Athens, Greece
  • 74 Center for Medical Genetics, Ghent University Hospita, Ghent, Belgium
  • 75 Unit of Hereditary Cancers, IRCCS AOU San Martino, Genova, Italy
  • 76 Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia
  • 77 Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
  • 78 Huntsman Cancer Institute and Department of Dermatology, University of Utah, Salt Lake City, Utah
  • 79 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. couch.fergus@mayo.edu
Cancer Res, 2017 Jun 01;77(11):2789-2799.
PMID: 28283652 DOI: 10.1158/0008-5472.CAN-16-2568

Abstract

Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789-99. ©2017 AACR.

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

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