Detectable clonal mosaicism and its relationship to aging and cancer.

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.

• Authors: 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 Stevens, Lauren 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 Sierrasesúmaga, 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 Jr, Neil E Caporaso, Margaret Tucker, Nathaniel Rothman, Luis A Pérez-Jurado, Stephen J Chanock
• Journal: Nature genetics (Nat Genet) Vol. 44 Issue 6 Pg. 651-8 (May 06 2012) ISSN: 1546-1718 [Electronic] United States
• PMID: 22561519 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)

Topics

• Aged
• Aging (genetics)
• Chromosome Aberrations
• Female
• Humans
• Male
• Middle Aged
• Mosaicism
• Neoplasms (genetics)
• Risk