Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions

Dareng EO 1 , Coetzee SG 2 , Tyrer JP 3 , Peng PC 2 , Rosenow W 4 , Chen S 5 Show all authors , Davis BD 5 , Dezem FS 2 , Seo JH 6 , Nameki R 7 , Reyes AL 2 , Aben KKH 8 , Anton-Culver H 9 , Antonenkova NN 10 , Aravantinos G 11 , Bandera EV 12 , Beane Freeman LE 13 , Beckmann MW 14 , Beeghly-Fadiel A 15 , Benitez J 16 , Bernardini MQ 17 , Bjorge L 18 , Black A 19 , Bogdanova NV 20 , Bolton KL 21 , Brenton JD 22 , Budzilowska A 23 , Butzow R 24 , Cai H 15 , Campbell I 25 , Cannioto R 26 , Chang-Claude J 27 , Chanock SJ 13 , Chen K 28 , Chenevix-Trench G 29 , AOCS Group 30 , Chiew YE 31 , Cook LS 32 , DeFazio A 33 , Dennis J 1 , Doherty JA 34 , Dörk T 35 , du Bois A 36 , Dürst M 37 , Eccles DM 38 , Ene G 17 , Fasching PA 14 , Flanagan JM 39 , Fortner RT 40 , Fostira F 41 , Gentry-Maharaj A 42 , Giles GG 43 , Goodman MT 44 , Gronwald J 45 , Haiman CA 46 , Håkansson N 47 , Heitz F 48 , Hildebrandt MAT 49 , Høgdall E 50 , Høgdall CK 51 , Huang RY 52 , Jensen A 53 , Jones ME 54 , Kang D 55 , Karlan BY 56 , Karnezis AN 57 , Kelemen LE 58 , Kennedy CJ 59 , Khusnutdinova EK 60 , Kiemeney LA 61 , Kjaer SK 62 , Kupryjanczyk J 23 , Labrie M 63 , Lambrechts D 64 , Larson MC 65 , Le ND 66 , Lester J 56 , Li L 28 , Lubiński J 45 , Lush M 1 , Marks JR 67 , Matsuo K 68 , May T 17 , McLaughlin JR 69 , McNeish IA 70 , Menon U 42 , Missmer S 71 , Modugno F 72 , Moffitt M 73 , Monteiro AN 74 , Moysich KB 75 , Narod SA 76 , Nguyen-Dumont T 77 , Odunsi K 78 , Olsson H 79 , Onland-Moret NC 80 , Park SK 81 , Pejovic T 82 , Permuth JB 74 , Piskorz A 22 , Prokofyeva D 83 , Riggan MJ 84 , Risch HA 85 , Rodríguez-Antona C 86 , Rossing MA 87 , Sandler DP 88 , Setiawan VW 46 , Shan K 89 , Song H 90 , Southey MC 91 , Steed H 92 , Sutphen R 93 , Swerdlow AJ 94 , Teo SH 95 , Terry KL 96 , Thompson PJ 97 , Vestrheim Thomsen LC 18 , Titus L 98 , Trabert B 19 , Travis R 99 , Tworoger SS 74 , Valen E 18 , Van Nieuwenhuysen E 100 , Edwards DV 101 , Vierkant RA 65 , Webb PM 102 , OPAL Study Group 102 , Weinberg CR 103 , Weise RM 104 , Wentzensen N 19 , White E 105 , Winham SJ 106 , Wolk A 107 , Woo YL 108 , Wu AH 109 , Yan L 110 , Yannoukakos D 41 , Zeinomar N 12 , Zheng W 15 , Ziogas A 9 , Berchuck A 84 , Goode EL 111 , Huntsman DG 112 , Pearce CL 113 , Ramus SJ 114 , Sellers TA 115 , Ovarian Cancer Association Consortium (OCAC) , Freedman ML 6 , Lawrenson K 7 , Schildkraut JM 116 , Hazelett D 117 , Plummer JT 5 , Kar S 118 , Jones MR 2 , Pharoah PDP 119 , Gayther SA 120

Affiliations 

  • 1 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  • 2 Center for Bioinformatics and Functional Genomics and the Cedars Sinai Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA, USA
  • 3 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
  • 4 3Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
  • 5 Center for Bioinformatics and Functional Genomics and the Cedars Sinai Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Applied Genomics, Computation and Translational Core, Cedars-Sinai Medical Center, Los Angeles, CA, USA
  • 6 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; The Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
  • 7 Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
  • 8 Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands; Netherlands Comprehensive Cancer Organisation, Utrecht, the Netherlands
  • 9 Department of Medicine, Genetic Epidemiology Research Institute, University of California, Irvine, Irvine, CA, USA
  • 10 N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus
  • 11 Agii Anargiri' Cancer Hospital, Athens, Greece
  • 12 Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
  • 13 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA
  • 14 Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany
  • 15 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
  • 16 Human Genetics Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
  • 17 Division of Gynecologic Oncology, University Health Network, Princess Margaret Hospital, Toronto, ON, Canada
  • 18 Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway; Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway
  • 19 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
  • 20 N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus; Department of Radiation Oncology, Hannover Medical School, Hannover, Germany; Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
  • 21 Division of Biology and Biomedical Sciences, Washington University, St. Louis, MO, USA
  • 22 Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
  • 23 Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
  • 24 Department of Pathology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  • 25 Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Center, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
  • 26 Cancer Pathology & Prevention, Division of Cancer Prevention and Population Sciences, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
  • 27 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • 28 Department of Epidemiology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
  • 29 Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
  • 30 Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Center, Melbourne, VIC, Australia; Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, NSW, Australia
  • 31 Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, NSW, Australia; Department of Gynaecological Oncology, Westmead Hospital, Sydney, NSW, Australia
  • 32 Epidemiology, School of Public Health, University of Colorado, Aurora, CO, USA; Community Health Sciences, University of Calgary, Calgary, AB, Canada
  • 33 Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, NSW, Australia; Department of Gynaecological Oncology, Westmead Hospital, Sydney, NSW, Australia; The Daffodil Centre, a joint venture with Cancer Council NSW, The University of Sydney, Sydney, NSW, Australia
  • 34 Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA
  • 35 Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
  • 36 Department of Gynecology and Gynecological Oncology; HSK, Dr. Horst-Schmidt Klinik, Wiesbaden, Wiesbaden, Germany; Department of Gynecology and Gynecologic Oncology, Evangelische Kliniken Essen-Mitte (KEM), Essen, Germany
  • 37 Department of Gynaecology, Jena University Hospital - Friedrich Schiller University, Jena, Germany
  • 38 Faculty of Medicine, University of Southampton, Southampton, UK
  • 39 Division of Cancer and Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, UK
  • 40 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 41 Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens, Greece
  • 42 MRC Clinical Trials Unit, Institute of Clinical Trials & Methodology, University College London, London, UK
  • 43 Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia
  • 44 Cancer Prevention and Control Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, CA, USA
  • 45 Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland
  • 46 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
  • 47 Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
  • 48 Department of Gynecology and Gynecological Oncology; HSK, Dr. Horst-Schmidt Klinik, Wiesbaden, Wiesbaden, Germany; Department of Gynecology and Gynecologic Oncology, Evangelische Kliniken Essen-Mitte (KEM), Essen, Germany; Center for Pathology, Evangelische Kliniken Essen-Mitte, Essen, Germany
  • 49 Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
  • 50 Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
  • 51 Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  • 52 Center For Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
  • 53 Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
  • 54 Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
  • 55 Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea; Cancer Research Institute, Seoul National University, Seoul, Korea
  • 56 David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, CA, USA
  • 57 Department of Pathology and Laboratory Medicine, UC Davis Medical Center, Sacramento, CA, USA
  • 58 Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
  • 59 Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, NSW, Australia; Department of Gynaecological Oncology, Westmead Hospital, Sydney, NSW, Australia; The University of Sydney, Sydney, NSW, Australia
  • 60 Institute of Biochemistry and Genetics of the Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia; Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, Russia
  • 61 Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
  • 62 Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
  • 63 Department of Immunology and Cell Biology, FMSS - Université de Sherbrooke, Sherbrooke, QC, Canada
  • 64 Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium; VIB Center for Cancer Biology, VIB, Leuven, Belgium
  • 65 Department of Quantitative Health Sciences, Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, USA
  • 66 Cancer Control Research, BC Cancer, Vancouver, BC, Canada
  • 67 Department of Surgery, Duke University Hospital, Durham, NC, USA
  • 68 Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan; Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
  • 69 Public Health Ontario, Samuel Lunenfeld Research Institute, Toronto, ON, Canada
  • 70 Division of Cancer and Ovarian Cancer Action Research Centre, Department Surgery & Cancer, Imperial College London, London, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
  • 71 Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
  • 72 Women's Cancer Research Center, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, PA, USA; Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
  • 73 Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
  • 74 Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA
  • 75 Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA
  • 76 Women's College Research Institute, University of Toronto, Toronto, ON, Canada
  • 77 Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia; Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia
  • 78 University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, USA; Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, USA
  • 79 Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden
  • 80 Julius Center for Health Sciences and Primary Care, University Utrecht, UMC Utrecht, Utrecht, the Netherlands
  • 81 Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea; Cancer Research Institute, Seoul National University, Seoul, Korea; Integrated Major in Innovative Medical Science, Seoul National University College of Medicine, Seoul, South Korea
  • 82 Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
  • 83 Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, Russia
  • 84 Department of Gynecologic Oncology, Duke University Hospital, Durham, NC, USA
  • 85 Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA
  • 86 Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain; Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain
  • 87 Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA
  • 88 Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA
  • 89 Department of Obstetrics and Gynaecology, Hebei Medical University, Fourth Hospital, Shijiazhuang, China
  • 90 Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  • 91 Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia; Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia
  • 92 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alberta, Edmonton, AB, Canada; Section of Gynecologic Oncology Surgery, Alberta Health Services, North Zone, Edmonton, AB, Canada
  • 93 Epidemiology Center, College of Medicine, University of South Florida, Tampa, FL, USA
  • 94 Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; Division of Breast Cancer Research, The Institute of Cancer Research, London, UK
  • 95 Breast Cancer Research Programme, Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia; Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 96 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics and Gyneoclogy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
  • 97 Samuel Oschin Comprehensive Cancer Institute, Cancer Prevention and Genetics Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA
  • 98 Muskie School of Public Service, University of Southern Maine, Portland, ME, USA
  • 99 Cancer Epidemiology Unit, University of Oxford, Oxford, UK
  • 100 Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Leuven Cancer Institute, Leuven, Belgium
  • 101 Division of Quantitative Sciences, Department of Obstetrics and Gynecology, Department of Biomedical Sciences, Women's Health Research, Vanderbilt University Medical Center, Nashville, TN, USA
  • 102 Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
  • 103 Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA
  • 104 Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
  • 105 Department of Epidemiology, University of Washington, Seattle, WA, USA; Fred Hutchinson Cancer Research Center, Seattle, WA, USA
  • 106 Department of Quantitative Health Sciences, Division of Computational Biology, Mayo Clinic, Rochester, MN, USA
  • 107 Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
  • 108 Department of Obstetrics and Gynaecology, University of Malaya Medical Centre, University of Malaya, Kuala Lumpur, Malaysia
  • 109 Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA
  • 110 Department of Molecular Biology, Hebei Medical University, Fourth Hospital, Shijiazhuang, China
  • 111 Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA
  • 112 Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada; Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC, Canada
  • 113 Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA; Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA
  • 114 School of Women's and Children's Health, Faculty of Medicine and Health, University of NSW Sydney, Sydney, NSW, Australia; Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, NSW, Australia
  • 115 TAS Consulting, LLC., Portland, OR, USA
  • 116 Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA
  • 117 Samuel Oschin Comprehensive Cancer Institute, The Center for Bioinformatics and Functional Biology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
  • 118 MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Section of Translational Epidemiology, Division of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
  • 119 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. Electronic address: [email protected]
  • 120 Center for Bioinformatics and Functional Genomics and the Cedars Sinai Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address: [email protected]
Am J Hum Genet, 2024 May 07.
PMID: 38723632 DOI: 10.1016/j.ajhg.2024.04.011

Abstract

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10-8) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10-5). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate <0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study.

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

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