Detectable clonal mosaicism and its relationship to aging and cancer

Kevin B. Jacobs, Meredith Yeager, Weiyin Zhou, Sholom Wacholder, Zhaoming Wang, Benjamin Rodriguez-Santiago, Amy Hutchinson, Xiang Deng, Chenwei Liu, Marie Josephe Horner, Michael Cullen, Caroline G. Epstein, Laurie Burdett, Michael C. Dean, Nilanjan Chatterjee, Joshua Sampson, Charles C. Chung, Joseph Kovaks, Susan M. Gapstur, Victoria L. StevensLauren T. Teras, Mia M. Gaudet, Demetrius Albanes, Stephanie J. Weinstein, Jarmo Virtamo, Philip R. Taylor, Neal D. Freedman, Christian C. Abnet, Alisa M. Goldstein, Nan Hu, Kai Yu, Jian Min Yuan, Linda Liao, Ti Ding, You Lin Qiao, Yu Tang Gao, Woon Puay Koh, Yong Bing Xiang, Ze Zhong Tang, Jin Hu Fan, Melinda C. Aldrich, Christopher Amos, William J. Blot, Cathryn H. Bock, Elizabeth M. Gillanders, Curtis C. Harris, Christopher A. Haiman, Brian E. Henderson, Laurence N. Kolonel, Loic Le Marchand, Lorna H. McNeill, Benjamin A. Rybicki, Ann G. Schwartz, Lisa B. Signorello, Margaret R. Spitz, John K. Wiencke, Margaret Wrensch, Xifeng Wu, Krista A. Zanetti, Regina G. Ziegler, Jonine D. Figueroa, Montserrat Garcia-Closas, Nuria Malats, Gaelle Marenne, Ludmila Prokunina-Olsson, Dalsu Baris, Molly Schwenn, Alison Johnson, Maria Teresa Landi, Lynn Goldin, Dario Consonni, Pier Alberto Bertazzi, Melissa Rotunno, Preetha Rajaraman, Ulrika Andersson, Laura E Beane Freeman, Christine D. Berg, Julie E. Buring, Mary A. Butler, Tania Carreon, Maria Feychting, Anders Ahlbom, J. Michael Gaziano, Graham G. Giles, Goran Hallmans, Susan E. Hankinson, Patricia Hartge, Roger Henriksson, Peter D. Inskip, Christoffer Johansen, Annelie Landgren, Roberta McKean-Cowdin, Dominique S. Michaud, Beatrice S. Melin, Ulrike Peters, Avima M. Ruder, Howard D. Sesso, Gianluca Severi, Xiao Ou Shu, Kala Visvanathan, Emily White, Alicja Wolk, Anne Zeleniuch-Jacquotte, Wei Zheng, Debra T. Silverman, Manolis Kogevinas, Juan R. Gonzalez, Olaya Villa, Donghui Li, Eric J. Duell, Harvey A. Risch, Sara H. Olson, Charles Kooperberg, Brian M. Wolpin, Li Jiao, Manal Hassan, William Wheeler, Alan A. Arslan, H. Bas Bueno-De-Mesquita, Charles S. Fuchs, Steven Gallinger, Myron D. Gross, Elizabeth A. Holly, Alison P. Klein, Andrea Lacroix, Margaret T. Mandelson, Gloria Petersen, Marie Christine Boutron-Ruault, Paige M. Bracci, Federico Canzian, Kenneth Chang, Michelle Cotterchio, Edward L. Giovannucci, Michael Goggins, Judith A Hoffman Bolton, Mazda Jenab, Kay Tee Khaw, Vittorio Krogh, Robert C. Kurtz, Robert R. McWilliams, Julie B. Mendelsohn, Kari G. Rabe, Elio Riboli, Anne Tjønneland, Geoffrey S. Tobias, Dimitrios Trichopoulos, Joanne W. Elena, Herbert Yu, Laufey Amundadottir, Rachael Z. Stolzenberg-Solomon, Peter Kraft, Fredrick Schumacher, Daniel Stram, Sharon A. Savage, Lisa Mirabello, Irene L. Andrulis, Jay S. Wunder, Ana Patiño García, Luis Sierrasesà maga, Donald A. Barkauskas, Richard G. Gorlick, Mark Purdue, Wong Ho Chow, Lee E. Moore, Kendra L. Schwartz, Faith G. Davis, Ann W. Hsing, Sonja I. Berndt, Amanda Black, Nicolas Wentzensen, Louise A. Brinton, Jolanta Lissowska, Beata Peplonska, Katherine A. McGlynn, Michael B. Cook, Barry I. Graubard, Christian P. Kratz, Mark H. Greene, Ralph L. Erickson, David J. Hunter, Gilles Thomas, Robert N. Hoover, Francisco X. Real, Joseph F. Fraumeni, Neil E. Caporaso, Margaret Tucker, Nathaniel Rothman, Luis A. Pérez-Jurado, Stephen J. Chanock

Research output: Contribution to journalArticlepeer-review

331 Scopus citations

Abstract

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10 -8). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10 -11). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.

Original languageEnglish (US)
Pages (from-to)651-658
Number of pages8
JournalNature Genetics
Volume44
Issue number6
DOIs
StatePublished - Jun 2012

Bibliographical note

Funding Information:
This research was supported by the Intramural Research Program and by contract number HHSN261200800001E of the US National Institutes of Health (NIH), NCI. Support for each contributing study is listed in the Supplementary Note. We thank C. Laurie and B. Weir for constructive discussion and a comparison of methodology and results for the GENEVA study. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Cancer Institute, the National Institute for Occupational Safety and Health or the Maryland Cancer Registry.

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