BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer

Shimelis H, Mesman RLS, Von Nicolai C, Ehlen A, Guidugli L, Martin C, Calleja FMGR, Meeks H, Hallberg E, Hinton J, Lilyquist J, Hu C, Aalfs CM, Aittomaki K, Andrulis I, Anton-Culver H, Arndt V, Beckmann M, Benitez J, Bogdanova NV, Bojesen SE, Bolla MK, Borresen-Dale AL, Brauch H, Brennan P, Brenner H, Broeks A, Brouwers B, Bruning T, Burwinkel B, Chang-Claude J, Chenevix-Trench G, Cheng CY, Choi JY, Collee JM, Cox A, Cross SS, Czene K, Darabi H, Dennis J, Dork T, Dos-Santos-Silva I, Dunning AM, Fasching P, Figueroa J, Flyger H, Garcia-Closas M, Giles GG, Glendon G, Guenel P, Haiman CA, Hall P, Hamann U, Hartman M, Hogervorst FB, Hollestelle A, Hopper JL, Ito H, Jakubowska A, Kang D, Kosma VM, Kristensen V, Lai KN, Lambrechts D, Le Marchand L, Li J, Lindblom A, Lophatananon A, Lubinski J, Machackova E, Mannermaa A, Margolin S, Marme F, Matsuo K, Miao H, Michailidou K, Milne RL, Muir K, Neuhausen SL, Nevanlinna H, Olson JE, Olswold C, Oosterwijk JJC, Osorio A, Peterlongo P, Peto J, Pharoah PDP, Pylkas K, Radice P, Rashid MU, Rhenius V, Rudolph A, Sangrajrang S, Sawyer EJ, Schmidt MK, Schoemaker MJ, Seynaeve C, Shah M, Shen CY, Shrubsole M, Shu XO, Slager S, Southey MC, Stram DO, Swerdlow A, Teo SH, Tomlinson I, Torres D, Truong T, Van Asperen CJ, Van Der Kolk LE, Wang Q, Winqvist R, Wu AH, Yu JC, Zheng W, Zheng Y, Leary J, Walker L, Foretova L, Fostira F, Claes KBM, Varesco L, Moghadasi S, Easton DF, Spurdle A, Devilee P, Vrieling H, Monteiro ANA, Goldgar DE, Carreira A, Vreeswijk MPG, Couch FJ (2017)


Publication Type: Journal article

Publication year: 2017

Journal

Book Volume: 77

Pages Range: 2789-2799

Journal Issue: 11

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.

Authors with CRIS profile

Involved external institutions

Mayo Clinic US United States (USA) (US) Leiden University NL Netherlands (NL) Institut Curie FR France (FR) University of Chicago US United States (USA) (US) University of Utah US United States (USA) (US) Helsingin yliopisto / University of Helsinki FI Finland (FI) Mount Sinai Hospital (MSH) CA Canada (CA) University of California Irvine US United States (USA) (US) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) ES Spain (ES) Medizinische Hochschule Hannover (MHH) / Hannover Medical School DE Germany (DE) Copenhagen University Hospital DK Denmark (DK) University of Cambridge GB United Kingdom (GB) Robert-Bosch-Krankenhaus DE Germany (DE) International Agency for Research on Cancer (IARC) FR France (FR) Antoni van Leeuwenhoek NL Netherlands (NL) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven BE Belgium (BE) Ruhr-Universität Bochum (RUB) DE Germany (DE) Ruprecht-Karls-Universität Heidelberg DE Germany (DE) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) AU Australia (AU) National University of Singapore (NUS) SG Singapore (SG) Seoul National University (SNU) / 서울대학교 KR Korea, Republic of (KR) Erasmus University Rotterdam (EUR) / Erasmus Universiteit Rotterdam NL Netherlands (NL) University of Sheffield GB United Kingdom (GB) Karolinska Institute SE Sweden (SE) London School of Hygiene and Tropical Medicine GB United Kingdom (GB) University of Edinburgh GB United Kingdom (GB) Center for Cancer Biology (CCB) (formerly Vesalius Research Center (VRC)) BE Belgium (BE) University of Hawaii (U.H.) US United States (USA) (US) University of Warwick GB United Kingdom (GB) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) PL Poland (PL) Masaryk Memorial Cancer Institute (MMCI) / Masarykův onkologický ústav (MOÚ) CZ Czech Republic (CZ) University of Eastern Finland FI Finland (FI) Nagoya University / 名古屋大学 JP Japan (JP) Cyprus Institute of Neurology and Genetics CY Cyprus (CY) University of Groningen / Rijksuniversiteit Groningen NL Netherlands (NL) University of Southern California (USC) US United States (USA) (US) University of Oxford GB United Kingdom (GB) École Polytechnique - Université Paris-Saclay FR France (FR) National Taiwan University Hospital (NTUH) / 國立台灣大學醫學院附設醫院 TW Taiwan (TW) Vanderbilt University US United States (USA) (US) National Cancer Institute (NCI) US United States (USA) (US) Cancer Council Victoria AU Australia (AU) Erasmus University Medical Center (MC) NL Netherlands (NL) The University of Melbourne AU Australia (AU) Aichi Cancer Center Research Institute JP Japan (JP) Cancer Research Initiatives Foundation (CARIF) / Cancer Research Malaysia (CRM) MY Malaysia (MY) City of Hope Medical Center US United States (USA) (US) IFOM - FIRC Institute of Molecular Oncology IT Italy (IT) Oulun Yliopisto / University of Oulo FI Finland (FI) Fondazione IRCCS: Istituto Nazionale dei Tumori IT Italy (IT) King’s College London GB United Kingdom (GB) The Institute of Cancer Research (ICR) GB United Kingdom (GB) China Medical University (CMU) / 中國醫藥大學 TW Taiwan (TW) Shanghai Center For Disease Control And Prevention (SCDC) CN China (CN) University of Sydney (USYD) AU Australia (AU) University of Otago NZ New Zealand (NZ) National Centre for Scientific Research (NCSR) "Demokritos" GR Greece (GR) University Hospital Ghent BE Belgium (BE) Ospedale San Martino (IRCCS AOU) IT Italy (IT) H. Lee Moffitt Cancer Center & Research Institute US United States (USA) (US)

How to cite

APA:

Shimelis, H., Mesman, R.L.S., Von Nicolai, C., Ehlen, A., Guidugli, L., Martin, C.,... Couch, F.J. (2017). BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer. Cancer Research, 77(11), 2789-2799. https://dx.doi.org/10.1158/0008-5472.CAN-16-2568

MLA:

Shimelis, Hermela, et al. "BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer." Cancer Research 77.11 (2017): 2789-2799.

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