Skip to Main Content

An official website of the United States government

Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element.

About this Publication
Title
Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element.
Pubmed ID
34146516 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Am J Hum Genet. 2021 Jul 1; Volume 108 (Issue 7): Pages 1190-1203
Authors
Baxter JS, Johnson N, Tomczyk K, Gillespie A, Maguire S, Brough R, Fachal L, Michailidou K, Bolla MK, Wang Q, Dennis J, Ahearn TU, Andrulis IL, Anton-Culver H, Antonenkova NN, Arndt V, Aronson KJ, Augustinsson A, Becher H, Beckmann MW, ...show more Behrens S, Benitez J, Bermisheva M, Bogdanova NV, Bojesen SE, Brenner H, Brucker SY, Cai Q, Campa D, Canzian F, Castelao JE, Chan TL, Chang-Claude J, Chanock SJ, Chenevix-Trench G, Choi JY, Clarke CL, NBCS Collaborators, Colonna S, Conroy DM, Couch FJ, Cox A, Cross SS, Czene K, Daly MB, Devilee P, Dörk T, Dossus L, Dwek M, Eccles DM, Ekici AB, Eliassen AH, Engel C, Fasching PA, Figueroa J, Flyger H, Gago-Dominguez M, Gao C, García-Closas M, García-Sáenz JA, Ghoussaini M, Giles GG, Goldberg MS, González-Neira A, Guénel P, Gündert M, Haeberle L, Hahnen E, Haiman CA, Hall P, Hamann U, Hartman M, Hatse S, Hauke J, Hollestelle A, Hoppe R, Hopper JL, Hou MF, kConFab Investigators, ABCTB Investigators, Ito H, Iwasaki M, Jager A, Jakubowska A, Janni W, John EM, Joseph V, Jung A, Kaaks R, Kang D, Keeman R, Khusnutdinova E, Kim SW, Kosma VM, Kraft P, Kristensen VN, Kubelka-Sabit K, Kurian AW, Kwong A, Lacey JV, Lambrechts D, Larson NL, Larsson SC, Le Marchand L, Lejbkowicz F, Li J, Long J, Lophatananon A, Lubiński J, Mannermaa A, Manoochehri M, Manoukian S, Margolin S, Matsuo K, Mavroudis D, Mayes R, Menon U, Milne RL, Mohd Taib NA, Muir K, Muranen TA, Murphy RA, Nevanlinna H, O'Brien KM, Offit K, Olson JE, Olsson H, Park SK, Park-Simon TW, Patel AV, Peterlongo P, Peto J, Plaseska-Karanfilska D, Presneau N, Pylkäs K, Rack B, Rennert G, Romero A, Ruebner M, Rüdiger T, Saloustros E, Sandler DP, Sawyer EJ, Schmidt MK, Schmutzler RK, Schneeweiss A, Schoemaker MJ, Shah M, Shen CY, Shu XO, Simard J, Southey MC, Stone J, Surowy H, Swerdlow AJ, Tamimi RM, Tapper WJ, Taylor JA, Teo SH, Teras LR, Terry MB, Toland AE, Tomlinson I, Truong T, Tseng CC, Untch M, Vachon CM, van den Ouweland AMW, Wang SS, Weinberg CR, Wendt C, Winham SJ, Winqvist R, Wolk A, Wu AH, Yamaji T, Zheng W, Ziogas A, Pharoah PDP, Dunning AM, Easton DF, Pettitt SJ, Lord CJ, Haider S, Orr N, Fletcher O
Affiliations
  • The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW7 3RP, UK. Electronic address: joseph.baxter@icr.ac.uk.
  • The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW7 3RP, UK.
  • Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Ireland BT7 1NN, UK.
  • The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW7 3RP, UK; The CRUK Gene Function Laboratory, The Institute of Cancer Research, London SW3 6JB, UK.
  • Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.
  • Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus; Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
  • Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20850, USA.
  • Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA 92617, USA.
...show more
  • N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk 223040, Belarus.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
  • Department of Public Health Sciences, and Cancer Research Institute, Queen's University, Kingston, ON K7L 3N6, Canada.
  • Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund 222 42, Sweden.
  • Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
  • Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg (FAU), Erlangen 91054, Germany.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
  • Biomedical Network on Rare Diseases (CIBERER), Madrid 28029, Spain; Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
  • Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa 450054, Russia.
  • N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk 223040, Belarus; Department of Radiation Oncology, Hannover Medical School, Hannover 30625, Germany; Gynaecology Research Unit, Hannover Medical School, Hannover 30625, Germany.
  • Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev 2730, Denmark; Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev 2730, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg 69120, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
  • Department of Gynecology and Obstetrics, University of Tübingen, Tübingen 72076, Germany.
  • Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Department of Biology, University of Pisa, Pisa 56126, Italy.
  • Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
  • Oncology and Genetics Unit, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo 36312, Spain.
  • Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong; Department of Molecular Pathology, Hong Kong Sanatorium and Hospital, Hong Kong.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
  • Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
  • Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 03080, Korea; Cancer Research Institute, Seoul National University, Seoul 03080, Korea; Institute of Health Policy and Management, Seoul National University Medical Research Center, Seoul 03080, Korea.
  • Westmead Institute for Medical Research, University of Sydney, Sydney, NSW 2145, Australia.
  • Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo 0379, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo 0450, Norway; Department of Research, Vestre Viken Hospital, Drammen 3019, Norway; Section for Breast and Endocrine Surgery, Department of Cancer, Division of Surgery, Cancer and Transplantation Medicine, Oslo University Hospital-Ullevål, Oslo 0450, Norway; Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo 0379, Norway; Department of Pathology, Akershus University Hospital, Lørenskog 1478, Norway; Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo 0379, Norway; Department of Oncology, Division of Surgery, Cancer and Transplantation Medicine, Oslo University Hospital-Radiumhospitalet, Oslo 0379, Norway; National Advisory Unit on Late Effects after Cancer Treatment, Oslo University Hospital-Radiumhospitalet, Oslo 0379, Norway; Department of Oncology, Akershus University Hospital, Lørenskog 1478, Norway; Breast Cancer Research Consortium, Oslo University Hospital, Oslo 0379, Norway.
  • Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
  • Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
  • Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Sheffield S10 2TN, UK.
  • Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield S10 2TN, UK.
  • Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 171 65, Sweden.
  • Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
  • Department of Pathology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands; Department of Human Genetics, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.
  • Gynaecology Research Unit, Hannover Medical School, Hannover 30625, Germany.
  • Nutrition and Metabolism Section, International Agency for Research on Cancer (IARC-WHO), Lyon 69372, France.
  • School of Life Sciences, University of Westminster, London W1B 2HW, UK.
  • Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK.
  • Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen 91054, Germany.
  • Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
  • Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig 04107, Germany; LIFE - Leipzig Research Centre for Civilization Diseases, University of Leipzig, Leipzig 04103, Germany.
  • Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg (FAU), Erlangen 91054, Germany; David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA 90095, USA.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20850, USA; Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh EH16 4UX, UK; Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh EH4 2XR, UK.
  • Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev 2730, Denmark.
  • Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela 15706, Spain; Moores Cancer Center, University of California San Diego, La Jolla, CA 92037, USA.
  • Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
  • Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid 28040, Spain.
  • Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK; Open Targets, Core Genetics Team, Wellcome Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
  • Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC 3004, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3010, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia.
  • Department of Medicine, McGill University, Montréal, QC H4A 3J1, Canada; Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montréal, QC H4A 3J1, Canada.
  • Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
  • Center for Research in Epidemiology and Population Health (CESP), Team Exposome and Heredity, INSERM, University Paris-Saclay, Villejuif 94805, France.
  • Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, Heidelberg 69120, Germany; Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany.
  • Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50937, Germany; Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50937, Germany.
  • Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
  • Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 171 65, Sweden; Department of Oncology, Södersjukhuset, Stockholm 118 83, Sweden.
  • Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
  • Saw Swee Hock School of Public Health, National University of Singapore, Singapore 119077, Singapore; Department of Surgery, National University Hospital, Singapore 119228, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore.
  • Laboratory of Experimental Oncology (LEO), Department of Oncology, KU Leuven, Leuven Cancer Institute, Leuven 3000, Belgium.
  • Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50937, Germany; Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50937, Germany; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50931, Germany.
  • Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam 3015 GD, the Netherlands.
  • Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart 70376, Germany; University of Tübingen, Tübingen 72074, Germany.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • Department of Surgery, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung 812, Taiwan.
  • Research Department, Peter MacCallum Cancer Center, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3000, Australia.
  • Australian Breast Cancer Tissue Bank, Westmead Institute for Medical Research, University of Sydney, Sydney, NSW 2145, Australia.
  • Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan; Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
  • Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo 104-0045, Japan.
  • Department of Genetics and Pathology, Pomeranian Medical University, Szczecin 71-252, Poland; Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin 71-252, Poland.
  • Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm 89075, Germany.
  • Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94304, USA.
  • Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 03080, Korea.
  • Division of Molecular Pathology, the Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam 1066 CX, the Netherlands.
  • Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa 450054, Russia; Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa 450000, Russia.
  • Department of Surgery, Daerim Saint Mary's Hospital, Seoul 07442, Korea.
  • Translational Cancer Research Area, University of Eastern Finland, Kuopio 70210, Finland; Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio 70210, Finland; Biobank of Eastern Finland, Kuopio University Hospital, Kuopio, Finland.
  • Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo 0450, Norway; Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo 0379, Norway.
  • Department of Histopathology and Cytology, Clinical Hospital Acibadem Sistina, Skopje 1000, Republic of North Macedonia.
  • Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong; Department of Surgery, The University of Hong Kong, Hong Kong; Department of Surgery and Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong.
  • Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA 91010, USA; City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA 91010, USA.
  • VIB Center for Cancer Biology, Leuven 3001, Belgium; Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven 3000, Belgium.
  • Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
  • Institute of Environmental Medicine, Karolinska Institutet, Stockholm 171 77, Sweden; Department of Surgical Sciences, Uppsala University, Uppsala 751 05, Sweden.
  • Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
  • Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa 35254, Israel.
  • Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore; Human Genetics Division, Genome Institute of Singapore, Singapore 138672, Singapore.
  • Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK.
  • Department of Genetics and Pathology, Pomeranian Medical University, Szczecin 71-252, Poland.
  • Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan 20133, Italy.
  • Department of Oncology, Södersjukhuset, Stockholm 118 83, Sweden; Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm 118 83, Sweden.
  • Department of Medical Oncology, University Hospital of Heraklion, Heraklion 711 10, Greece.
  • Institute of Clinical Trials & Methodology, University College London, London WC1V 6LJ, UK.
  • Breast Cancer Research Unit, University Malaya Cancer Research Institute, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia.
  • Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki 00290, Finland.
  • School of Population and Public Health, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Cancer Control Research, BC Cancer, Vancouver, BC V5Z 1L3, Canada.
  • Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA.
  • Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Cancer Research Institute, Seoul National University, Seoul 03080, Korea; Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 03080, Korea; Convergence Graduate Program in Innovative Medical Science, Seoul National University College of Medicine, Seoul 03080, Korea.
  • Department of Population Science, American Cancer Society, Atlanta, GA 30303, USA.
  • Genome Diagnostics Program, IFOM - the FIRC Institute of Molecular Oncology, Milan 20139, Italy.
  • Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
  • Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', MASA, Skopje 1000, Republic of North Macedonia.
  • Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu 90570, Finland; Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu 90570, Finland.
  • Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid 28222, Spain.
  • Institute of Pathology, Staedtisches Klinikum Karlsruhe, Karlsruhe 76133, Germany.
  • Department of Oncology, University Hospital of Larissa, Larissa 411 10, Greece.
  • School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, King's College London, London, UK.
  • Division of Molecular Pathology, the Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam 1066 CX, the Netherlands; Division of Psychosocial Research and Epidemiology, the Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam 1066 CX, the Netherlands.
  • Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, Heidelberg 69120, Germany; National Center for Tumor Diseases, University Hospital and German Cancer Research Center, Heidelberg 69120, Germany.
  • Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.
  • Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan; School of Public Health, China Medical University, Taichung, Taiwan.
  • Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC G1V 4G2, Canada.
  • Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC 3004, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia; Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3010, Australia; Genetic Epidemiology Group, School of Population and Global Health, University of Western Australia, Perth, WA 6000, Australia.
  • Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, Heidelberg 69120, Germany.
  • Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK; Division of Breast Cancer Research, The Institute of Cancer Research, London SW7 3RP, UK.
  • Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Population Health Sciences, Weill Cornell Medicine, New York, NY 10065, USA.
  • Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA; Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA.
  • Breast Cancer Research Programme, Cancer Research Malaysia, Subang Jaya, Selangor 47500, Malaysia; Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia.
  • Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032, USA.
  • Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH 43210, USA.
  • Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK; Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford OX3 7BN, UK.
  • Department of Gynecology and Obstetrics, Helios Clinics Berlin-Buch, Berlin 13125, Germany.
  • Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN 55905, USA.
  • Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam 3015 GD, the Netherlands.
  • Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA.
  • Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm 118 83, Sweden.
  • Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA.
  • Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
  • The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW7 3RP, UK. Electronic address: olivia.fletcher@icr.ac.uk.
Abstract

A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10-31).

Related CDAS Studies
Related CDAS Projects