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Nat Commun. 2016 Jun 13;7:11843. doi: 10.1038/ncomms11843.

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

Machiela MJ1, Zhou W1,2, Karlins E1,2, Sampson JN1, Freedman ND1, Yang Q1,2, Hicks B1,2, Dagnall C1,2, Hautman C1,2, Jacobs KB2,3, Abnet CC1, Aldrich MC4,5, Amos C6, Amundadottir LT1, Arslan AA7,8,9, Beane-Freeman LE1, Berndt SI1, Black A1, Blot WJ5,10, Bock CH11, Bracci PM12, Brinton LA1, Bueno-de-Mesquita HB13,14,15,16, Burdett L1,2, Buring JE17, Butler MA18, Canzian F19, Carreón T18, Chaffee KG20, Chang IS21, Chatterjee N1, Chen C22, Chen C23, Chen K24, Chung CC1,2, Cook LS25, Crous Bou M23,26, Cullen M1,2, Davis FG27, De Vivo I23,26, Ding T28, Doherty J29, Duell EJ30, Epstein CG1, Fan JH31, Figueroa JD1, Fraumeni JF1, Friedenreich CM32, Fuchs CS26,33, Gallinger S34, Gao YT35, Gapstur SM36, Garcia-Closas M37, Gaudet MM36, Gaziano JM38,39, Giles GG40, Gillanders EM41, Giovannucci EL26,42, Goldin L1, Goldstein AM1, Haiman CA43, Hallmans G44, Hankinson SE26,45, Harris CC46, Henriksson R47, Holly EA12, Hong YC48, Hoover RN1, Hsiung CA49, Hu N1, Hu W1, Hunter DJ23,26,50, Hutchinson A1,2, Jenab M51, Johansen C52,53, Khaw KT54, Kim HN55, Kim YH56, Kim YT57, Klein AP58, Klein R59, Koh WP60,61, Kolonel LN62, Kooperberg C22, Kraft P23, Krogh V63, Kurtz RC64, LaCroix A22, Lan Q1, Landi MT1, Marchand LL62, Li D65, Liang X66, Liao LM1, Lin D67,68, Liu J69,70, Lissowska J71, Lu L72, Magliocco AM73, Malats N74, Matsuo K75, McNeill LH76, McWilliams RR77, Melin BS47, Mirabello L1, Moore L1, Olson SH66, Orlow I66, Park JY78, Patiño-Garcia A79, Peplonska B80, Peters U22, Petersen GM20, Pooler L81, Prescott J23,26, Prokunina-Olsson L1, Purdue MP1, Qiao YL82, Rajaraman P1, Real FX74,83, Riboli E84, Risch HA72, Rodriguez-Santiago B83,85,86, Ruder AM18, Savage SA1, Schumacher F43, Schwartz AG11, Schwartz KL87, Seow A61, Wendy Setiawan V43, Severi G40,88, Shen H89,90, Sheng X81, Shin MH91, Shu XO92, Silverman DT1, Spitz MR93, Stevens VL36, Stolzenberg-Solomon R1, Stram D43, Tang ZZ28, Taylor PR1, Teras LR36, Tobias GS1, Van Den Berg D43, Visvanathan K94, Wacholder S1, Wang JC95,96, Wang Z1,2, Wentzensen N1, Wheeler W97, White E22, Wiencke JK98, Wolpin BM26,33, Wong MP99, Wu C67,68, Wu T100, Wu X101, Wu YL102, Wunder JS102, Xia L81, Yang HP1, Yang PC103, Yu K1, Zanetti KA41, Zeleniuch-Jacquotte A9,104, Zheng W5, Zhou B105, Ziegler RG1, Perez-Jurado LA83,85, Caporaso NE1, Rothman N1, Tucker M1, Dean MC1, Yeager M1,2, Chanock SJ1.

Author information

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
Bioinformed, LLC, Gaithersburg, Maryland 20877, USA.
4
Department of Thoracic Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
5
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
6
Department of Epidemiology, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
7
Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York 10016, USA.
8
Department of Environmental Medicine, New York University School of Medicine, New York, New York 10016, USA.
9
New York University Cancer Institute, New York, New York 10016, USA.
10
International Epidemiology Institute, Rockville, Maryland 20850, USA.
11
Karmanos Cancer Institute and Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
12
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California 94143, USA.
13
Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), 3721 Bilthoven, The Netherlands.
14
Department of Gastroenterology and Hepatology, University Medical Center, 3584 CX Utrecht, The Netherlands.
15
Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London SW7 2AZ, UK.
16
Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia.
17
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
18
National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Cincinnati, Ohio 45226, USA.
19
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
20
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA.
21
National Institute of Cancer Research, National Health Research Institutes, Zhunan 35053, Taiwan.
22
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
23
Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
24
Department of Epidemiology and Biostatistics, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300040, China.
25
University of New Mexico, Albuquerque, New Mexico 87131, USA.
26
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
27
Department of Public Health Sciences, School of Public Health, University of Alberta, Edmonton, Alberta, Canada T6G 2R3.
28
Shanxi Cancer Hospital, Taiyuan, Shanxi 030013, China.
29
Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire 03755, USA.
30
Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute, Catalan Institute of Oncology (ICO-IDIBELL), 08908 Barcelona, Spain.
31
Shanghai Cancer Institute, Shanghai 200032, China.
32
Department of Population Health Research, Cancer Control Alberta, Alberta Health Services, Calgary, Alberta, Canada T2N 2T9.
33
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
34
Fred A Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada M5G 1X5.
35
Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotaong University School of Medicine, Shanghai 200032, China.
36
Epidemiology Research Program, American Cancer Society, Atlanta, Georgia 30303, USA.
37
Division of Genetics and Epidemiology, and Breakthrough Breast Cancer Centre, Institute for Cancer Research, London SM2 5NG, UK.
38
Divisions of Preventive Medicine and Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
39
Massachusetts Veterans Epidemiology Research and Information Center/VA Cooperative Studies Programs, Veterans Affairs Boston Healthcare System, Boston, Massachusetts 02130, USA.
40
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.
41
Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Maryland 20892, USA.
42
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
43
Department of Preventive Medicine, Biostatistics Division, Keck School of Medicine at the University of Southern California, Los Angeles, California 90033, USA.
44
Department of Public Health and Clinical Medicine/Nutritional Research, Umeå University, 901 87 Umeå, Sweden.
45
Division of Biostatistics and Epidemiology, University of Massachusetts School of Public Health and Health Sciences, Amherst, Massachusetts 01003, USA.
46
Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
47
Department of Radiation Sciences, Oncology, Umeå University, 901 87 Umeå, Sweden.
48
Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 151-742, Republic of Korea.
49
Institute of Population Health Sciences, National Health Research Institutes, Zhunan 35053, Taiwan.
50
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
51
International Agency for Research on Cancer (IARC-WHO), 69372 Lyon, France.
52
Oncology, Finsen Centre, Rigshospitalet, 2100 Copenhagen, Denmark.
53
Unit of Survivorship Research, The Danish Cancer Society Research Centre, 2100 Copenhagen, Denmark.
54
School of Clinical Medicine, University of Cambridge, Cambridge CB2 1TN, UK.
55
Center for Creative Biomedical Scientists, Chonnam National University, Gwangju 500-757, Republic of Korea.
56
Department of Internal Medicine, Division of Oncology/Hematology, College of Medicine, Korea University Anam Hospital, Seoul 151-742, Republic of Korea.
57
Department of Thoracic and Cardiovascular Surgery, Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
58
Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
59
Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York, 10065, USA.
60
Duke-NUS Graduate Medical School, Singapore 169857, Singapore.
61
Saw Swee Hock School of Public Health, National University of Singapore, Singapore 119077, Singapore.
62
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii 96813, USA.
63
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano 20133, Italy.
64
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
65
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
66
Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
67
Department of Etiology &Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
68
State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
69
Department of Human Genetics, Genome Institute of Singapore 138672, Singapore.
70
School of Life Sciences, Anhui Medical University, Hefei 230032, China.
71
Department of Cancer Epidemiology and Prevention, Maria Sklodowska-Curie Cancer Center and Institute of Oncology, Warsaw 02-781, Poland.
72
Yale School of Public Health, New Haven, Connecticut 06510, USA.
73
H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.
74
Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
75
Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan.
76
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.
77
Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA.
78
Lung Cancer Center, Kyungpook National University Medical Center, Daegu 101, Republic of Korea.
79
Department of Pediatrics, University Clinic of Navarra, Universidad de Navarra, IdiSNA, Navarra Institute for Health Research, Pamplona 31080, Spain.
80
Nofer Institute of Occupational Medicine, Lodz 91-348, Poland.
81
University of Southern California, Los Angeles, California 90007, USA.
82
Department of Epidemiology, Cancer Institute (Hospital), Chinese Academy of Medical Sciences, Beijing 100730, China.
83
Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona 08002, Spain.
84
Division of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London SW7 2AZ, UK.
85
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, 28029, Spain.
86
Quantitative Genomic Medicine Laboratory, qGenomics, Barcelona 08003, Spain.
87
Karmanos Cancer Institute and Department of Family Medicine and Public Health Sciences, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
88
Human Genetics Foundation (HuGeF), Torino, 10126, Italy.
89
Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing 210029, China.
90
Department of Epidemiology, Nanjing Medical University School of Public Health, Nanjing 210029, China.
91
Department of Preventive Medicine, Chonnam National University Medical School, Gwanju 501-746, Republic of Korea.
92
Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
93
Baylor College of Medicine, Houston, Texas 77030, USA.
94
Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21218, USA.
95
Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200433, China.
96
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China.
97
Information Management Services Inc., Calverton, Maryland, 20904, USA.
98
University of California San Francisco, San Francisco, California 94143, USA.
99
Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
100
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.
101
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
102
Guangdong Lung Cancer Institute, Guangdong General Hospital &Guangdong Academy of Medical Sciences, Guangzhou 515200, China.
103
Division of Urologic Surgery, Washington University School of Medicine, St Louis, Missouri 63110, USA.
104
Department of Population Health, New York University School of Medicine, New York, New York 10016, USA.
105
Department of Epidemiology, School of Public Health, China Medical University, Shenyang 110001, China.

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.

PMID:
27291797
PMCID:
PMC4909985
DOI:
10.1038/ncomms11843
[Indexed for MEDLINE]
Free PMC Article

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