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Common variants in breast cancer risk loci predispose to distinct tumor subtypes.

About this Publication
Title
Common variants in breast cancer risk loci predispose to distinct tumor subtypes.
Pubmed ID
34983606 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Breast Cancer Res. 2022 Jan 4; Volume 24 (Issue 1): Pages 2
Authors
Ahearn TU , Zhang H , Michailidou K , Milne RL , Bolla MK , Dennis J , Dunning AM , Lush M , Wang Q , Andrulis IL , Anton-Culver H , Arndt V , Aronson KJ , Auer PL , Augustinsson A , Baten A , Becher H , Behrens S , Benitez J , Bermisheva M , ...show more Blomqvist C , Bojesen SE , Bonanni B , Børresen-Dale AL , Brauch H , Brenner H , Brooks-Wilson A , Brüning T , Burwinkel B , Buys SS , Canzian F , Castelao JE , Chang-Claude J , Chanock SJ , Chenevix-Trench G , Clarke CL , NBCS Collaborators , Collée JM , Cox A , Cross SS , Czene K , Daly MB , Devilee P , Dörk T , Dwek M , Eccles DM , Evans DG , Fasching PA , Figueroa J , Floris G , Gago-Dominguez M , Gapstur SM , García-Sáenz JA , Gaudet MM , Giles GG , Goldberg MS , González-Neira A , Alnæs GIG , Grip M , Guénel P , Haiman CA , Hall P , Hamann U , Harkness EF , Heemskerk-Gerritsen BAM , Holleczek B , Hollestelle A , Hooning MJ , Hoover RN , Hopper JL , Howell A , ABCTB Investigators , kConFab/AOCS Investigators , Jakimovska M , Jakubowska A , John EM , Jones ME , Jung A , Kaaks R , Kauppila S , Keeman R , Khusnutdinova E , Kitahara CM , Ko YD , Koutros S , Kristensen VN , Krüger U , Kubelka-Sabit K , Kurian AW , Kyriacou K , Lambrechts D , Lee DG , Lindblom A , Linet M , Lissowska J , Llaneza A , Lo WY , MacInnis RJ , Mannermaa A , Manoochehri M , Margolin S , Martinez ME , McLean C , Meindl A , Menon U , Nevanlinna H , Newman WG , Nodora J , Offit K , Olsson H , Orr N , Park-Simon TW , Patel AV , Peto J , Pita G , Plaseska-Karanfilska D , Prentice R , Punie K , Pylkäs K , Radice P , Rennert G , Romero A , Rüdiger T , Saloustros E , Sampson S , Sandler DP , Sawyer EJ , Schmutzler RK , Schoemaker MJ , Schöttker B , Sherman ME , Shu XO , Smichkoska S , Southey MC , Spinelli JJ , Swerdlow AJ , Tamimi RM , Tapper WJ , Taylor JA , Teras LR , Terry MB , Torres D , Troester MA , Vachon CM , van Deurzen CHM , van Veen EM , Wagner P , Weinberg CR , Wendt C , Wesseling J , Winqvist R , Wolk A , Yang XR , Zheng W , Couch FJ , Simard J , Kraft P , Easton DF , Pharoah PDP , Schmidt MK , García-Closas M , Chatterjee N
Affiliations
  • Division of Cancer Epidemiology and GeneticsDepartment of Health and Human Services, Medical Center Drive, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.
  • Institute of Neurology & Genetics, Biostatistics Unit, Nicosia, Cyprus.
  • Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
  • Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
  • Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
  • Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Department of Public Health Sciences, and Cancer Research Institute, Queen's University, Kingston, ON, Canada.
  • Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
...show more
  • Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
  • Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
  • Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  • Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia.
  • Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
  • Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, Milan, Italy.
  • Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway.
  • Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
  • Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
  • Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute, Ruhr University Bochum (IPA), Bochum, Germany.
  • Molecular Epidemiology Group, German Cancer Research Center (DKFZ), C080, Heidelberg, Germany.
  • Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT, USA.
  • Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain.
  • Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
  • Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia.
  • Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • Department of Oncology and Metabolism, Sheffield Institute for Nucleic Acids (SInFoNiA), University of Sheffield, Sheffield, UK.
  • Department of Neuroscience, Academic Unit of Pathology, University of Sheffield, Sheffield, UK.
  • Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
  • Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
  • Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
  • Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
  • School of Life Sciences, University of Westminster, London, UK.
  • Faculty of Medicine, University of Southampton, Southampton, UK.
  • North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
  • Department of Gynecology and Obstetrics Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany.
  • Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, UK.
  • Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain.
  • Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
  • Medical Oncology Department, Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain.
  • Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montréal, QC, Canada.
  • Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, Finland.
  • Center for Research in Epidemiology and Population Health (CESP), Team Exposome and Heredity, INSERM, University Paris-Saclay, Villejuif, France.
  • Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
  • Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
  • Saarland Cancer Registry, Saarbrücken, Germany.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
  • Division of Cancer Sciences, University of Manchester, Manchester, UK.
  • Research Centre for Genetic Engineering and Biotechnology "Georgi D. Efremov", MASA, Skopje, Republic of North Macedonia.
  • Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
  • Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA, USA.
  • Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
  • Department of Pathology, Oulu University Hospital, University of Oulu, Oulu, Finland.
  • Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
  • Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
  • Department of Internal Medicine, Johanniter Kliniken Bonn, Johanniter Krankenhaus, Bonn, Germany.
  • Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
  • Department of Histopathology and Cytology, Clinical Hospital Acibadem Sistina, Skopje, Republic of North Macedonia.
  • Cyprus School of Molecular Medicine, Institute of Neurology & Genetics, Nicosia, Cyprus.
  • Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium.
  • Cancer Control Research, BC Cancer, Vancouver, BC, Canada.
  • Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
  • Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland.
  • General and Gastroenterology Surgery Service, Hospital Universitario Central de Asturias, Oviedo, Spain.
  • Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
  • Department of Oncology, Södersjukhuset, Stockholm, Sweden.
  • Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
  • Anatomical Pathology, The Alfred Hospital, Melbourne, VIC, Australia.
  • Department of Gynecology and Obstetrics, University of Munich, Campus Großhadern, Munich, Germany.
  • Institute of Clinical Trials & Methodology, University College London, London, UK.
  • Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
  • Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Ireland, UK.
  • Department of Non-Communicable Disease Epidemiology, School of Hygiene and Tropical Medicine, London, UK.
  • Human Genotyping-CEGEN Unit, Human Cancer Genetic Program, Spanish National Cancer Research Centre, Madrid, Spain.
  • Department of General Medical Oncology and Multidisciplinary Breast Center, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
  • Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, University of Oulu, Biocenter Oulu, Oulu, Finland.
  • Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale Dei Tumori (INT), Milan, Italy.
  • Technion Faculty of Medicine, Clalit National Cancer Control Center, Carmel Medical Center, Haifa, Israel.
  • Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.
  • Institute of Pathology, Staedtisches Klinikum Karlsruhe, Karlsruhe, Germany.
  • Department of Oncology, University Hospital of Larissa, Larissa, Greece.
  • Prevent Breast Cancer Centre and Nightingale Breast Screening Centre, Manchester University NHS Foundation Trust, Manchester, UK.
  • Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
  • School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, King's College London, London, UK.
  • Center for Integrated Oncology (CIO), Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany.
  • Department of Health Sciences Research, Mayo Clinic College of Medicine, Jacksonville, FL, USA.
  • Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • Medical Faculty, Ss. Cyril and Methodius University in Skopje, University Clinic of Radiotherapy and Oncology, Skopje, Republic of North Macedonia.
  • Population Oncology, BC Cancer, Vancouver, BC, Canada.
  • Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA.
  • Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
  • Department of Epidemiology, Gillings School of Global Public Health and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
  • Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
  • Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
  • Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
  • Genomics Center, Department of Molecular Medicine, Centre Hospitalier Universitaire de Québec, Université Laval Research Center, Université Laval, Québec City, QC, Canada.
  • Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • Division of Cancer Epidemiology and GeneticsDepartment of Health and Human Services, Medical Center Drive, National Cancer Institute, National Institutes of Health, Rockville, MD, USA. montserrat.garcia-closas@nih.gov.
  • Department of Biostatistics, Bloomberg School of Public Health, John Hopkins University, Baltimore, MD, USA.
Abstract

BACKGROUND: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear.

METHODS: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes.

RESULTS: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions.

CONCLUSION: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.

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