Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 May 6;44(6):651-8.
doi: 10.1038/ng.2270.

Detectable clonal mosaicism and its relationship to aging and cancer

Kevin B Jacobs  1 , 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
Affiliations

Detectable clonal mosaicism and its relationship to aging and cancer

Kevin B Jacobs et al. Nat Genet. .

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Characteristics of detectable clonal mosaic events
Detectable clonal mosaic events plotted by proportion of abnormal cells (p) and Log R Ratio (LRR) for 681 events in 517 individuals.
Figure 2
Figure 2. Circular genomic plot of detectable clonal mosaic events
Genomic location of detectable clonal mosaic events. Outer rings are the autosomes 1 to 22. Yellow region denotes events of copy neutral loss of heterozygosity. Blue region denotes copy gain events. Red region denotes copy loss events. Panel A includes events in cancer free controls. Panel B includes events in cancer cases.
Figure 3
Figure 3. Frequency of detectable clonal mosaic events by age and cancer status
Analysis excluded 1,000 individuals with unknown age at DNA collection. 95% confidence intervals are shown.
See this image and copyright information in PMC

Comment in

  • Exploring the variation within.
    Macosko EZ, McCarroll SA. Macosko EZ, et al. Nat Genet. 2012 May 29;44(6):614-6. doi: 10.1038/ng.2311. Nat Genet. 2012. PMID: 22641203

Similar articles

  • Detectable clonal mosaicism from birth to old age and its relationship to cancer.
    Laurie CC, Laurie CA, Rice K, Doheny KF, Zelnick LR, McHugh CP, Ling H, Hetrick KN, Pugh EW, Amos C, Wei Q, Wang LE, Lee JE, Barnes KC, Hansel NN, Mathias R, Daley D, Beaty TH, Scott AF, Ruczinski I, Scharpf RB, Bierut LJ, Hartz SM, Landi MT, Freedman ND, Goldin LR, Ginsburg D, Li J, Desch KC, Strom SS, Blot WJ, Signorello LB, Ingles SA, Chanock SJ, Berndt SI, Le Marchand L, Henderson BE, Monroe KR, Heit JA, de Andrade M, Armasu SM, Regnier C, Lowe WL, Hayes MG, Marazita ML, Feingold E, Murray JC, Melbye M, Feenstra B, Kang JH, Wiggs JL, Jarvik GP, McDavid AN, Seshan VE, Mirel DB, Crenshaw A, Sharopova N, Wise A, Shen J, Crosslin DR, Levine DM, Zheng X, Udren JI, Bennett S, Nelson SC, Gogarten SM, Conomos MP, Heagerty P, Manolio T, Pasquale LR, Haiman CA, Caporaso N, Weir BS. Laurie CC, et al. Nat Genet. 2012 May 6;44(6):642-50. doi: 10.1038/ng.2271. Nat Genet. 2012. PMID: 22561516 Free PMC article.
  • Characterization of large structural genetic mosaicism in human autosomes.
    Machiela MJ, Zhou W, Sampson JN, Dean MC, Jacobs KB, Black A, Brinton LA, Chang IS, Chen C, Chen C, Chen K, Cook LS, Crous Bou M, De Vivo I, Doherty J, Friedenreich CM, Gaudet MM, Haiman CA, Hankinson SE, Hartge P, Henderson BE, Hong YC, Hosgood HD 3rd, Hsiung CA, Hu W, Hunter DJ, Jessop L, Kim HN, Kim YH, Kim YT, Klein R, Kraft P, Lan Q, Lin D, Liu J, Le Marchand L, Liang X, Lissowska J, Lu L, Magliocco AM, Matsuo K, Olson SH, Orlow I, Park JY, Pooler L, Prescott J, Rastogi R, Risch HA, Schumacher F, Seow A, Setiawan VW, Shen H, Sheng X, Shin MH, Shu XO, VanDen Berg D, Wang JC, Wentzensen N, Wong MP, Wu C, Wu T, Wu YL, Xia L, Yang HP, Yang PC, Zheng W, Zhou B, Abnet CC, Albanes D, Aldrich MC, Amos C, Amundadottir LT, Berndt SI, Blot WJ, Bock CH, Bracci PM, Burdett L, Buring JE, Butler MA, Carreón T, Chatterjee N, Chung CC, Cook MB, Cullen M, Davis FG, Ding T, Duell EJ, Epstein CG, Fan JH, Figueroa JD, Fraumeni JF Jr, Freedman ND, Fuchs CS, Gao YT, Gapstur SM, Patiño-Garcia A, Garcia-Closas M, Gaziano JM, Giles GG, Gillanders EM, Giovannucci EL, Goldin L, Goldstein AM, Greene MH, Hallmans G, Harris CC, Henriksson R, Holly EA, Hoover RN, Hu N, Hutchinson A, Jenab M, Johansen C, Kha… See abstract for full author list ➔ Machiela MJ, et al. Am J Hum Genet. 2015 Mar 5;96(3):487-97. doi: 10.1016/j.ajhg.2015.01.011. Am J Hum Genet. 2015. PMID: 25748358 Free PMC article.
  • Mosaic 13q14 deletions in peripheral leukocytes of non-hematologic cancer cases and healthy controls.
    Machiela MJ, Zhou W, Caporaso N, Dean M, Gapstur SM, Goldin L, Stevens VL, Yeager M, Chanock SJ. Machiela MJ, et al. J Hum Genet. 2016 May;61(5):411-8. doi: 10.1038/jhg.2015.166. Epub 2016 Jan 14. J Hum Genet. 2016. PMID: 26763882 Free PMC article.
  • Detectable clonal mosaicism in the human genome.
    Machiela MJ, Chanock SJ. Machiela MJ, et al. Semin Hematol. 2013 Oct;50(4):348-59. doi: 10.1053/j.seminhematol.2013.09.001. Semin Hematol. 2013. PMID: 24246702 Free PMC article. Review.
  • The ageing genome, clonal mosaicism and chronic disease.
    Machiela MJ, Chanock SJ. Machiela MJ, et al. Curr Opin Genet Dev. 2017 Feb;42:8-13. doi: 10.1016/j.gde.2016.12.002. Epub 2017 Jan 6. Curr Opin Genet Dev. 2017. PMID: 28068559 Free PMC article. Review.
See all similar articles

Cited by

See all "Cited by" articles

References

    1. Youssoufian H, Pyeritz RE. Mechanisms and consequences of somatic mosaicism in humans. Nat Rev Genet. 2002;3:748–58. - PubMed
    1. Notini AJ, Craig JM, White SJ. Copy number variation and mosaicism. Cytogenet Genome Res. 2008;123:270–7. - PubMed
    1. Hsu LY, et al. Proposed guidelines for diagnosis of chromosome mosaicism in amniocytes based on data derived from chromosome mosaicism and pseudomosaicism studies. Prenat Diagn. 1992;12:555–73. - PubMed
    1. Menten B, et al. Emerging patterns of cryptic chromosomal imbalance in patients with idiopathic mental retardation and multiple congenital anomalies: a new series of 140 patients and review of published reports. J Med Genet. 2006;43:625–33. - PMC - PubMed
    1. Lu XY, et al. Genomic imbalances in neonates with birth defects: high detection rates by using chromosomal microarray analysis. Pediatrics. 2008;122:1310–8. - PMC - PubMed

Publication types