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

Mitchell J. Machiela, Weiyin Zhou, Eric Karlins, Joshua N. Sampson, Neal D. Freedman, Qi Yang, Belynda Hicks, Casey Dagnall, Christopher Hautman, Kevin B. Jacobs, Christian C. Abnet, Melinda C. Aldrich, Christopher Amos, Laufey T. Amundadottir, Alan A. Arslan, Laura E. Beane-Freeman, Sonja I. Berndt, Amanda Black, William J. Blot, Cathryn H. Bock, Paige M. Bracci, Louise A. Brinton, H Bas Bueno- de-Mesquita, Laurie Burdett, Julie E. Buring, Mary A. Butler, Federico Canzian, Tania Carreón, Kari G. Chaffee, I-Shou Chang, Nilanjan Chatterjee, Chu Chen, Constance Chen, Kexin Chen, Charles C. Chung, Linda S. Cook, Marta Crous Bou, Michael Cullen, Faith G. Davis, Immaculata De Vivo, Ti Ding, Jennifer Doherty, Eric J. Duell, Caroline G. Epstein, Jin-Hu Fan, Jonine D. Figueroa, Joseph F. Fraumeni, Christine M. Friedenreich, Charles S. Fuchs, Steven Gallinger, Yu-Tang Gao, Susan M. Gapstur, Montserrat Garcia-Closas, Mia M. Gaudet, J. Michael Gaziano, Graham G. Giles, Elizabeth M. Gillanders, Edward L. Giovannucci, Lynn Goldin, Alisa M. Goldstein, Christopher A. Haiman, Goran Hallmans, Susan E. Hankinson, Curtis C. Harris, Roger Henriksson, Elizabeth A. Holly, Yun-Chul Hong, Robert N. Hoover, Chao A. Hsiung, Nan Hu, Wei Hu, David J. Hunter, Amy Hutchinson, Mazda Jenab, Christoffer Johansen, Kay-Tee Khaw, Hee Nam Kim, Yeul Hong Kim, Young Tae Kim, Alison P. Klein, Robert Klein, Woon-Puay Koh, Laurence N. Kolonel, Charles Kooperberg, Peter Kraft, Vittorio Krogh, Robert C. Kurtz, Andrea LaCroix, Qing Lan, Maria Teresa Landi, Loic Le Marchand, Donghui Li, Xiaolin Liang, Linda M. Liao, Dongxin Lin, Jianjun Liu, Jolanta Lissowska, Lingeng Lu, Anthony M. Magliocco, Nuria Malats, Keitaro Matsuo, Lorna H. McNeill, Robert R. McWilliams, Beatrice S. Melin, Lisa Mirabello, Lee Moore, Sara H. Olson, Irene Orlow, Jae Yong Park, Ana Patiño-Garcia, Beata Peplonska, Ulrike Peters, Gloria M. Petersen, Loreall Pooler, Jennifer Prescott, Ludmila Prokunina-Olsson, Mark P. Purdue, You-Lin Qiao, Preetha Rajaraman, Francisco X. Real, Elio Riboli, Harvey A. Risch, Benjamin Rodriguez-Santiago, Avima M. Ruder, Sharon A. Savage, Fredrick Schumacher, Ann G. Schwartz, Kendra L. Schwartz, Adeline Seow, Veronica Wendy Setiawan, Gianluca Severi, Hongbing Shen, Xin Sheng, Min-Ho Shin, Xiao-Ou Shu, Debra T. Silverman, Margaret R. Spitz, Victoria L. Stevens, Rachael Stolzenberg-Solomon, Daniel Stram, Ze-Zhong Tang, Philip R. Taylor, Lauren R. Teras, Geoffrey S. Tobias, David Van Den Berg, Kala Visvanathan, Sholom Wacholder, Jiu-Cun Wang, Zhaoming Wang, Nicolas Wentzensen, William Wheeler, Emily White, John K. Wiencke, Brian M. Wolpin, Maria Pik Wong, Chen Wu, Tangchun Wu, Xifeng Wu, Yi-Long Wu, Jay S. Wunder, Lucy Xia, Hannah P. Yang, Pan-Chyr Yang, Kai Yu, Krista A. Zanetti, Anne Zeleniuch-Jacquotte, Wei Zheng, Baosen Zhou, Regina G. Ziegler, Luis A. Perez-Jurado, Neil E. Caporaso, Nathaniel Rothman, Margaret Tucker, Michael C. Dean, Meredith Yeager and Stephen J. Chanock ()
Additional contact information
Mitchell J. Machiela: National Cancer Institute (NCI), National Institutes of Health (NIH)
Weiyin Zhou: National Cancer Institute (NCI), National Institutes of Health (NIH)
Eric Karlins: National Cancer Institute (NCI), National Institutes of Health (NIH)
Joshua N. Sampson: National Cancer Institute (NCI), National Institutes of Health (NIH)
Neal D. Freedman: National Cancer Institute (NCI), National Institutes of Health (NIH)
Qi Yang: National Cancer Institute (NCI), National Institutes of Health (NIH)
Belynda Hicks: National Cancer Institute (NCI), National Institutes of Health (NIH)
Casey Dagnall: National Cancer Institute (NCI), National Institutes of Health (NIH)
Christopher Hautman: National Cancer Institute (NCI), National Institutes of Health (NIH)
Kevin B. Jacobs: Cancer Genomics Research Laboratory, National Cancer Institute, Leidos Biomedical Research Inc.
Christian C. Abnet: National Cancer Institute (NCI), National Institutes of Health (NIH)
Melinda C. Aldrich: Vanderbilt University School of Medicine
Christopher Amos: The University of Texas MD Anderson Cancer Center
Laufey T. Amundadottir: National Cancer Institute (NCI), National Institutes of Health (NIH)
Alan A. Arslan: New York University School of Medicine
Laura E. Beane-Freeman: National Cancer Institute (NCI), National Institutes of Health (NIH)
Sonja I. Berndt: National Cancer Institute (NCI), National Institutes of Health (NIH)
Amanda Black: National Cancer Institute (NCI), National Institutes of Health (NIH)
William J. Blot: Vanderbilt Epidemiology Center, Vanderbilt University Medical Center
Cathryn H. Bock: Wayne State University School of Medicine
Paige M. Bracci: University of California San Francisco
Louise A. Brinton: National Cancer Institute (NCI), National Institutes of Health (NIH)
H Bas Bueno- de-Mesquita: National Institute for Public Health and the Environment (RIVM)
Laurie Burdett: National Cancer Institute (NCI), National Institutes of Health (NIH)
Julie E. Buring: Brigham and Women’s Hospital
Mary A. Butler: National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention
Federico Canzian: German Cancer Research Center (DKFZ)
Tania Carreón: National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention
Kari G. Chaffee: Mayo Clinic
I-Shou Chang: National Institute of Cancer Research, National Health Research Institutes
Nilanjan Chatterjee: National Cancer Institute (NCI), National Institutes of Health (NIH)
Chu Chen: Fred Hutchinson Cancer Research Center
Constance Chen: Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health
Kexin Chen: Tianjin Medical University Cancer Institute and Hospital
Charles C. Chung: National Cancer Institute (NCI), National Institutes of Health (NIH)
Linda S. Cook: University of New Mexico
Marta Crous Bou: Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health
Michael Cullen: National Cancer Institute (NCI), National Institutes of Health (NIH)
Faith G. Davis: School of Public Health, University of Alberta
Immaculata De Vivo: Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health
Ti Ding: Shanxi Cancer Hospital
Jennifer Doherty: Geisel School of Medicine, Dartmouth College
Eric J. Duell: Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute, Catalan Institute of Oncology (ICO-IDIBELL)
Caroline G. Epstein: National Cancer Institute (NCI), National Institutes of Health (NIH)
Jin-Hu Fan: Shanghai Cancer Institute
Jonine D. Figueroa: National Cancer Institute (NCI), National Institutes of Health (NIH)
Joseph F. Fraumeni: National Cancer Institute (NCI), National Institutes of Health (NIH)
Christine M. Friedenreich: Cancer Control Alberta, Alberta Health Services
Charles S. Fuchs: Brigham and Women's Hospital and Harvard Medical School
Steven Gallinger: Fred A Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute
Yu-Tang Gao: Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotaong University School of Medicine
Susan M. Gapstur: Epidemiology Research Program, American Cancer Society
Montserrat Garcia-Closas: and Breakthrough Breast Cancer Centre, Institute for Cancer Research
Mia M. Gaudet: Epidemiology Research Program, American Cancer Society
J. Michael Gaziano: Brigham and Women’s Hospital and Harvard Medical School
Graham G. Giles: Cancer Epidemiology Centre, Cancer Council Victoria & Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne
Elizabeth M. Gillanders: National Cancer Institute
Edward L. Giovannucci: Brigham and Women's Hospital and Harvard Medical School
Lynn Goldin: National Cancer Institute (NCI), National Institutes of Health (NIH)
Alisa M. Goldstein: National Cancer Institute (NCI), National Institutes of Health (NIH)
Christopher A. Haiman: Keck School of Medicine at the University of Southern California
Goran Hallmans: Umeå University
Susan E. Hankinson: Brigham and Women's Hospital and Harvard Medical School
Curtis C. Harris: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute
Roger Henriksson: Oncology, Umeå University
Elizabeth A. Holly: University of California San Francisco
Yun-Chul Hong: Seoul National University College of Medicine
Robert N. Hoover: National Cancer Institute (NCI), National Institutes of Health (NIH)
Chao A. Hsiung: Institute of Population Health Sciences, National Health Research Institutes
Nan Hu: National Cancer Institute (NCI), National Institutes of Health (NIH)
Wei Hu: National Cancer Institute (NCI), National Institutes of Health (NIH)
David J. Hunter: Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health
Amy Hutchinson: National Cancer Institute (NCI), National Institutes of Health (NIH)
Mazda Jenab: International Agency for Research on Cancer (IARC-WHO)
Christoffer Johansen: Oncology, Finsen Centre
Kay-Tee Khaw: School of Clinical Medicine, University of Cambridge
Hee Nam Kim: Center for Creative Biomedical Scientists, Chonnam National University
Yeul Hong Kim: College of Medicine, Korea University Anam Hospital
Young Tae Kim: Cancer Research Institute, Seoul National University College of Medicine
Alison P. Klein: The Johns Hopkins University School of Medicine
Robert Klein: Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center
Woon-Puay Koh: Duke-NUS Graduate Medical School
Laurence N. Kolonel: Epidemiology Program, University of Hawaii Cancer Center
Charles Kooperberg: Fred Hutchinson Cancer Research Center
Peter Kraft: Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health
Vittorio Krogh: Fondazione IRCCS Istituto Nazionale dei Tumori
Robert C. Kurtz: Memorial Sloan-Kettering Cancer Center
Andrea LaCroix: Fred Hutchinson Cancer Research Center
Qing Lan: National Cancer Institute (NCI), National Institutes of Health (NIH)
Maria Teresa Landi: National Cancer Institute (NCI), National Institutes of Health (NIH)
Loic Le Marchand: Epidemiology Program, University of Hawaii Cancer Center
Donghui Li: The University of Texas MD Anderson Cancer Center
Xiaolin Liang: Memorial Sloan-Kettering Cancer Center
Linda M. Liao: National Cancer Institute (NCI), National Institutes of Health (NIH)
Dongxin Lin: Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
Jianjun Liu: Genome Institute of Singapore
Jolanta Lissowska: Maria Sklodowska-Curie Cancer Center and Institute of Oncology
Lingeng Lu: Yale School of Public Health
Anthony M. Magliocco: H. Lee Moffitt Cancer Center and Research Institute
Nuria Malats: Spanish National Cancer Research Centre (CNIO)
Keitaro Matsuo: Aichi Cancer Center Research Institute
Lorna H. McNeill: Cancer Prevention and Population Sciences, and Center for Community-Engaged Translational Research, Duncan Family Institute, The University of Texas MD Anderson Cancer Center
Robert R. McWilliams: Mayo Clinic
Beatrice S. Melin: Oncology, Umeå University
Lisa Mirabello: National Cancer Institute (NCI), National Institutes of Health (NIH)
Lee Moore: National Cancer Institute (NCI), National Institutes of Health (NIH)
Sara H. Olson: Memorial Sloan-Kettering Cancer Center
Irene Orlow: Memorial Sloan-Kettering Cancer Center
Jae Yong Park: Lung Cancer Center, Kyungpook National University Medical Center
Ana Patiño-Garcia: University Clinic of Navarra, Universidad de Navarra, IdiSNA, Navarra Institute for Health Research
Beata Peplonska: Nofer Institute of Occupational Medicine
Ulrike Peters: Fred Hutchinson Cancer Research Center
Gloria M. Petersen: Mayo Clinic
Loreall Pooler: University of Southern California
Jennifer Prescott: Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health
Ludmila Prokunina-Olsson: National Cancer Institute (NCI), National Institutes of Health (NIH)
Mark P. Purdue: National Cancer Institute (NCI), National Institutes of Health (NIH)
You-Lin Qiao: Cancer Institute (Hospital), Chinese Academy of Medical Sciences
Preetha Rajaraman: National Cancer Institute (NCI), National Institutes of Health (NIH)
Francisco X. Real: Spanish National Cancer Research Centre (CNIO)
Elio Riboli: School of Public Health, Imperial College London
Harvey A. Risch: Yale School of Public Health
Benjamin Rodriguez-Santiago: Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra
Avima M. Ruder: National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention
Sharon A. Savage: National Cancer Institute (NCI), National Institutes of Health (NIH)
Fredrick Schumacher: Keck School of Medicine at the University of Southern California
Ann G. Schwartz: Wayne State University School of Medicine
Kendra L. Schwartz: Wayne State University School of Medicine
Adeline Seow: Saw Swee Hock School of Public Health, National University of Singapore
Veronica Wendy Setiawan: Keck School of Medicine at the University of Southern California
Gianluca Severi: Cancer Epidemiology Centre, Cancer Council Victoria & Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne
Hongbing Shen: Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University
Xin Sheng: University of Southern California
Min-Ho Shin: Chonnam National University Medical School
Xiao-Ou Shu: Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center
Debra T. Silverman: National Cancer Institute (NCI), National Institutes of Health (NIH)
Margaret R. Spitz: Baylor College of Medicine
Victoria L. Stevens: Epidemiology Research Program, American Cancer Society
Rachael Stolzenberg-Solomon: National Cancer Institute (NCI), National Institutes of Health (NIH)
Daniel Stram: Keck School of Medicine at the University of Southern California
Ze-Zhong Tang: Shanxi Cancer Hospital
Philip R. Taylor: National Cancer Institute (NCI), National Institutes of Health (NIH)
Lauren R. Teras: Epidemiology Research Program, American Cancer Society
Geoffrey S. Tobias: National Cancer Institute (NCI), National Institutes of Health (NIH)
David Van Den Berg: Keck School of Medicine at the University of Southern California
Kala Visvanathan: Johns Hopkins Bloomberg School of Public Health
Sholom Wacholder: National Cancer Institute (NCI), National Institutes of Health (NIH)
Jiu-Cun Wang: Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University
Zhaoming Wang: National Cancer Institute (NCI), National Institutes of Health (NIH)
Nicolas Wentzensen: National Cancer Institute (NCI), National Institutes of Health (NIH)
William Wheeler: Information Management Services Inc.
Emily White: Fred Hutchinson Cancer Research Center
John K. Wiencke: University of California San Francisco
Brian M. Wolpin: Brigham and Women's Hospital and Harvard Medical School
Maria Pik Wong: Li Ka Shing Faculty of Medicine, The University of Hong Kong
Chen Wu: Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
Tangchun Wu: Institute of Occupational Medicine and Ministry of Education Key Laboratory for Environment and Health, School of Public Health, Huazhong University of Science and Technology
Xifeng Wu: The University of Texas MD Anderson Cancer Center
Yi-Long Wu: Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences
Jay S. Wunder: Washington University School of Medicine
Lucy Xia: University of Southern California
Hannah P. Yang: National Cancer Institute (NCI), National Institutes of Health (NIH)
Pan-Chyr Yang: National Taiwan University College of Medicine
Kai Yu: National Cancer Institute (NCI), National Institutes of Health (NIH)
Krista A. Zanetti: National Cancer Institute
Anne Zeleniuch-Jacquotte: New York University Cancer Institute
Wei Zheng: Vanderbilt Epidemiology Center, Vanderbilt University Medical Center
Baosen Zhou: School of Public Health, China Medical University
Regina G. Ziegler: National Cancer Institute (NCI), National Institutes of Health (NIH)
Luis A. Perez-Jurado: Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra
Neil E. Caporaso: National Cancer Institute (NCI), National Institutes of Health (NIH)
Nathaniel Rothman: National Cancer Institute (NCI), National Institutes of Health (NIH)
Margaret Tucker: National Cancer Institute (NCI), National Institutes of Health (NIH)
Michael C. Dean: National Cancer Institute (NCI), National Institutes of Health (NIH)
Meredith Yeager: National Cancer Institute (NCI), National Institutes of Health (NIH)
Stephen J. Chanock: National Cancer Institute (NCI), National Institutes of Health (NIH)

Nature Communications, 2016, vol. 7, issue 1, 1-9

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11843

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