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Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome

Machiela MJ 1 , Zhou W 1 , Karlins E 1 , Sampson JN 1 , Freedman ND 1 , Yang Q 1 Show all authors , Hicks B 1 , Dagnall C 1 , Hautman C 1 , Jacobs KB 2 , Abnet CC 1 , Aldrich MC 3 , Amos C 4 , Amundadottir LT 1 , Arslan AA 5 , Beane-Freeman LE 1 , Berndt SI 1 , Black A 1 , Blot WJ 6 , Bock CH 7 , Bracci PM 8 , Brinton LA 1 , Bueno-de-Mesquita HB 9 , Burdett L 1 , Buring JE 10 , Butler MA 11 , Canzian F 12 , Carreón T 11 , Chaffee KG 13 , Chang IS 14 , Chatterjee N 1 , Chen C 15 , Chen C 16 , Chen K 17 , Chung CC 1 , Cook LS 18 , Crous Bou M 16 , Cullen M 1 , Davis FG 19 , De Vivo I 16 , Ding T 20 , Doherty J 21 , Duell EJ 22 , Epstein CG 1 , Fan JH 23 , Figueroa JD 1 , Fraumeni JF 1 , Friedenreich CM 24 , Fuchs CS 25 , Gallinger S 26 , Gao YT 27 , Gapstur SM 28 , Garcia-Closas M 29 , Gaudet MM 28 , Gaziano JM 30 , Giles GG 31 , Gillanders EM 32 , Giovannucci EL 25 , Goldin L 1 , Goldstein AM 1 , Haiman CA 33 , Hallmans G 34 , Hankinson SE 25 , Harris CC 35 , Henriksson R 36 , Holly EA 8 , Hong YC 37 , Hoover RN 1 , Hsiung CA 38 , Hu N 1 , Hu W 1 , Hunter DJ 16 , Hutchinson A 1 , Jenab M 39 , Johansen C 40 , Khaw KT 41 , Kim HN 42 , Kim YH 43 , Kim YT 44 , Klein AP 45 , Klein R 46 , Koh WP 47 , Kolonel LN 48 , Kooperberg C 15 , Kraft P 16 , Krogh V 49 , Kurtz RC 50 , LaCroix A 15 , Lan Q 1 , Landi MT 1 , Marchand LL 48 , Li D 51 , Liang X 52 , Liao LM 1 , Lin D 53 , Liu J 54 , Lissowska J 55 , Lu L 56 , Magliocco AM 57 , Malats N 58 , Matsuo K 59 , McNeill LH 60 , McWilliams RR 61 , Melin BS 36 , Mirabello L 1 , Moore L 1 , Olson SH 52 , Orlow I 52 , Park JY 62 , Patiño-Garcia A 63 , Peplonska B 64 , Peters U 15 , Petersen GM 13 , Pooler L 65 , Prescott J 16 , Prokunina-Olsson L 1 , Purdue MP 1 , Qiao YL 66 , Rajaraman P 1 , Real FX 58 , Riboli E 67 , Risch HA 56 , Rodriguez-Santiago B 68 , Ruder AM 11 , Savage SA 1 , Schumacher F 33 , Schwartz AG 7 , Schwartz KL 69 , Seow A 70 , Wendy Setiawan V 33 , Severi G 31 , Shen H 71 , Sheng X 65 , Shin MH 72 , Shu XO 73 , Silverman DT 1 , Spitz MR 74 , Stevens VL 28 , Stolzenberg-Solomon R 1 , Stram D 33 , Tang ZZ 20 , Taylor PR 1 , Teras LR 28 , Tobias GS 1 , Van Den Berg D 33 , Visvanathan K 75 , Wacholder S 1 , Wang JC 76 , Wang Z 1 , Wentzensen N 1 , Wheeler W 77 , White E 15 , Wiencke JK 78 , Wolpin BM 25 , Wong MP 79 , Wu C 53 , Wu T 80 , Wu X 81 , Wu YL 82 , Wunder JS 82 , Xia L 65 , Yang HP 1 , Yang PC 83 , Yu K 1 , Zanetti KA 32 , Zeleniuch-Jacquotte A 84 , Zheng W 6 , Zhou B 85 , Ziegler RG 1 , Perez-Jurado LA 68 , Caporaso NE 1 , Rothman N 1 , Tucker M 1 , Dean MC 1 , Yeager M 1 , Chanock SJ 1

Affiliations 

  • 1 Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA
  • 2 Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research Inc., Bethesda, Maryland 20892, USA
  • 3 Department of Thoracic Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
  • 4 Department of Epidemiology, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
  • 5 Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York 10016, USA
  • 6 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
  • 7 Karmanos Cancer Institute and Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
  • 8 Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California 94143, USA
  • 9 Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), 3721 Bilthoven, The Netherlands
  • 10 Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA
  • 11 National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Cincinnati, Ohio 45226, USA
  • 12 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
  • 13 Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA
  • 14 National Institute of Cancer Research, National Health Research Institutes, Zhunan 35053, Taiwan
  • 15 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA
  • 16 Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts 02115, USA
  • 17 Department of Epidemiology and Biostatistics, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300040, China
  • 18 University of New Mexico, Albuquerque, New Mexico 87131, USA
  • 19 Department of Public Health Sciences, School of Public Health, University of Alberta, Edmonton, Alberta, Canada T6G 2R3
  • 20 Shanxi Cancer Hospital, Taiyuan, Shanxi 030013, China
  • 21 Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire 03755, USA
  • 22 Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute, Catalan Institute of Oncology (ICO-IDIBELL), 08908 Barcelona, Spain
  • 23 Shanghai Cancer Institute, Shanghai 200032, China
  • 24 Department of Population Health Research, Cancer Control Alberta, Alberta Health Services, Calgary, Alberta, Canada T2N 2T9
  • 25 Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
  • 26 Fred A Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada M5G 1X5
  • 27 Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotaong University School of Medicine, Shanghai 200032, China
  • 28 Epidemiology Research Program, American Cancer Society, Atlanta, Georgia 30303, USA
  • 29 Division of Genetics and Epidemiology, and Breakthrough Breast Cancer Centre, Institute for Cancer Research, London SM2 5NG, UK
  • 30 Divisions of Preventive Medicine and Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
  • 31 Cancer Epidemiology Centre, Cancer Council Victoria &Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria 3010, Australia
  • 32 Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Maryland 20892, USA
  • 33 Department of Preventive Medicine, Biostatistics Division, Keck School of Medicine at the University of Southern California, Los Angeles, California 90033, USA
  • 34 Department of Public Health and Clinical Medicine/Nutritional Research, Umeå University, 901 87 Umeå, Sweden
  • 35 Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA
  • 36 Department of Radiation Sciences, Oncology, Umeå University, 901 87 Umeå, Sweden
  • 37 Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 151-742, Republic of Korea
  • 38 Institute of Population Health Sciences, National Health Research Institutes, Zhunan 35053, Taiwan
  • 39 International Agency for Research on Cancer (IARC-WHO), 69372 Lyon, France
  • 40 Oncology, Finsen Centre, Rigshospitalet, 2100 Copenhagen, Denmark
  • 41 School of Clinical Medicine, University of Cambridge, Cambridge CB2 1TN, UK
  • 42 Center for Creative Biomedical Scientists, Chonnam National University, Gwangju 500-757, Republic of Korea
  • 43 Department of Internal Medicine, Division of Oncology/Hematology, College of Medicine, Korea University Anam Hospital, Seoul 151-742, Republic of Korea
  • 44 Department of Thoracic and Cardiovascular Surgery, Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
  • 45 Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
  • 46 Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York, 10065, USA
  • 47 Duke-NUS Graduate Medical School, Singapore 169857, Singapore
  • 48 Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii 96813, USA
  • 49 Fondazione IRCCS Istituto Nazionale dei Tumori, Milano 20133, Italy
  • 50 Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA
  • 51 Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
  • 52 Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA
  • 53 Department of Etiology &Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
  • 54 Department of Human Genetics, Genome Institute of Singapore 138672, Singapore
  • 55 Department of Cancer Epidemiology and Prevention, Maria Sklodowska-Curie Cancer Center and Institute of Oncology, Warsaw 02-781, Poland
  • 56 Yale School of Public Health, New Haven, Connecticut 06510, USA
  • 57 H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
  • 58 Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain
  • 59 Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan
  • 60 Department of Health Disparities Research, Division of OVP, Cancer Prevention and Population Sciences, and Center for Community-Engaged Translational Research, Duncan Family Institute, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
  • 61 Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA
  • 62 Lung Cancer Center, Kyungpook National University Medical Center, Daegu 101, Republic of Korea
  • 63 Department of Pediatrics, University Clinic of Navarra, Universidad de Navarra, IdiSNA, Navarra Institute for Health Research, Pamplona 31080, Spain
  • 64 Nofer Institute of Occupational Medicine, Lodz 91-348, Poland
  • 65 University of Southern California, Los Angeles, California 90007, USA
  • 66 Department of Epidemiology, Cancer Institute (Hospital), Chinese Academy of Medical Sciences, Beijing 100730, China
  • 67 Division of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London SW7 2AZ, UK
  • 68 Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona 08002, Spain
  • 69 Karmanos Cancer Institute and Department of Family Medicine and Public Health Sciences, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
  • 70 Saw Swee Hock School of Public Health, National University of Singapore, Singapore 119077, Singapore
  • 71 Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing 210029, China
  • 72 Department of Preventive Medicine, Chonnam National University Medical School, Gwanju 501-746, Republic of Korea
  • 73 Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
  • 74 Baylor College of Medicine, Houston, Texas 77030, USA
  • 75 Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21218, USA
  • 76 Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200433, China
  • 77 Information Management Services Inc., Calverton, Maryland, 20904, USA
  • 78 University of California San Francisco, San Francisco, California 94143, USA
  • 79 Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
  • 80 Institute of Occupational Medicine and Ministry of Education Key Laboratory for Environment and Health, School of Public Health, Huazhong University of Science and Technology, Wuhan 430400, China
  • 81 Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
  • 82 Guangdong Lung Cancer Institute, Guangdong General Hospital &Guangdong Academy of Medical Sciences, Guangzhou 515200, China
  • 83 Division of Urologic Surgery, Washington University School of Medicine, St Louis, Missouri 63110, USA
  • 84 New York University Cancer Institute, New York, New York 10016, USA
  • 85 Department of Epidemiology, School of Public Health, China Medical University, Shenyang 110001, China
Nat Commun, 2016 06 13;7:11843.
PMID: 27291797 DOI: 10.1038/ncomms11843

Abstract

To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.

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

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