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. 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 SierrasesÃ 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

doi:10.1038/ng.2270

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 SierrasesÃ 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 journal › Article › peer-review

484 Citations (Scopus)

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 language	English
Pages (from-to)	651-658
Number of pages	8
Journal	Nature Genetics
Volume	44
Issue number	6
DOIs	https://doi.org/10.1038/ng.2270
Publication status	Published or Issued - Jun 2012
Externally published	Yes

ASJC Scopus subject areas

Genetics

Access to Document

10.1038/ng.2270

Cite this

Jacobs, K. B., Yeager, M., Zhou, W., Wacholder, S., Wang, Z., Rodriguez-Santiago, B., Hutchinson, A., Deng, X., Liu, C., Horner, M. J., Cullen, M., Epstein, C. G., Burdett, L., Dean, M. C., Chatterjee, N., Sampson, J., Chung, C. C., Kovaks, J., Gapstur, S. M., ... Chanock, S. J. (2012). Detectable clonal mosaicism and its relationship to aging and cancer. Nature Genetics, 44(6), 651-658. https://doi.org/10.1038/ng.2270

@article{90a7ddc92763487a8dac90f33f251fb6,

title = "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.",

author = "Jacobs, {Kevin B.} and Meredith Yeager and Weiyin Zhou and Sholom Wacholder and Zhaoming Wang and Benjamin Rodriguez-Santiago and Amy Hutchinson and Xiang Deng and Chenwei Liu and Horner, {Marie Josephe} and Michael Cullen and Epstein, {Caroline G.} and Laurie Burdett and Dean, {Michael C.} and Nilanjan Chatterjee and Joshua Sampson and Chung, {Charles C.} and Joseph Kovaks and Gapstur, {Susan M.} and Stevens, {Victoria L.} and Teras, {Lauren T.} and Gaudet, {Mia M.} and Demetrius Albanes and Weinstein, {Stephanie J.} and Jarmo Virtamo and Taylor, {Philip R.} and Freedman, {Neal D.} and Abnet, {Christian C.} and Goldstein, {Alisa M.} and Nan Hu and Kai Yu and Yuan, {Jian Min} and Linda Liao and Ti Ding and Qiao, {You Lin} and Gao, {Yu Tang} and Koh, {Woon Puay} and Xiang, {Yong Bing} and Tang, {Ze Zhong} and Fan, {Jin Hu} and Aldrich, {Melinda C.} and Christopher Amos and Blot, {William J.} and Bock, {Cathryn H.} and Gillanders, {Elizabeth M.} and Harris, {Curtis C.} and Haiman, {Christopher A.} and Henderson, {Brian E.} and Kolonel, {Laurence N.} and {Le Marchand}, Loic and McNeill, {Lorna H.} and Rybicki, {Benjamin A.} and Schwartz, {Ann G.} and Signorello, {Lisa B.} and Spitz, {Margaret R.} and Wiencke, {John K.} and Margaret Wrensch and Xifeng Wu and Zanetti, {Krista A.} and Ziegler, {Regina G.} and Figueroa, {Jonine D.} and Montserrat Garcia-Closas and Nuria Malats and Gaelle Marenne and Ludmila Prokunina-Olsson and Dalsu Baris and Molly Schwenn and Alison Johnson and Landi, {Maria Teresa} and Lynn Goldin and Dario Consonni and Bertazzi, {Pier Alberto} and Melissa Rotunno and Preetha Rajaraman and Ulrika Andersson and Freeman, {Laura E.Beane} and Berg, {Christine D.} and Buring, {Julie E.} and Butler, {Mary A.} and Tania Carreon and Maria Feychting and Anders Ahlbom and Gaziano, {J. Michael} and Giles, {Graham G.} and Goran Hallmans and Hankinson, {Susan E.} and Patricia Hartge and Roger Henriksson and Inskip, {Peter D.} and Christoffer Johansen and Annelie Landgren and Roberta McKean-Cowdin and Michaud, {Dominique S.} and Melin, {Beatrice S.} and Ulrike Peters and Ruder, {Avima M.} and Sesso, {Howard D.} and Gianluca Severi and Shu, {Xiao Ou} and Kala Visvanathan and Emily White and Alicja Wolk and Anne Zeleniuch-Jacquotte and Wei Zheng and Silverman, {Debra T.} and Manolis Kogevinas and Gonzalez, {Juan R.} and Olaya Villa and Donghui Li and Duell, {Eric J.} and Risch, {Harvey A.} and Olson, {Sara H.} and Charles Kooperberg and Wolpin, {Brian M.} and Li Jiao and Manal Hassan and William Wheeler and Arslan, {Alan A.} and Bueno-De-Mesquita, {H. Bas} and Fuchs, {Charles S.} and Steven Gallinger and Gross, {Myron D.} and Holly, {Elizabeth A.} and Klein, {Alison P.} and Andrea Lacroix and Mandelson, {Margaret T.} and Gloria Petersen and Boutron-Ruault, {Marie Christine} and Bracci, {Paige M.} and Federico Canzian and Kenneth Chang and Michelle Cotterchio and Giovannucci, {Edward L.} and Michael Goggins and Bolton, {Judith A.Hoffman} and Mazda Jenab and Khaw, {Kay Tee} and Vittorio Krogh and Kurtz, {Robert C.} and McWilliams, {Robert R.} and Mendelsohn, {Julie B.} and Rabe, {Kari G.} and Elio Riboli and Anne Tj{\o}nneland and Tobias, {Geoffrey S.} and Dimitrios Trichopoulos and Elena, {Joanne W.} and Herbert Yu and Laufey Amundadottir and Stolzenberg-Solomon, {Rachael Z.} and Peter Kraft and Fredrick Schumacher and Daniel Stram and Savage, {Sharon A.} and Lisa Mirabello and Andrulis, {Irene L.} and Wunder, {Jay S.} and Garc{\'i}a, {Ana Pati{\~n}o} and {Sierrases{\~A} maga}, Luis and Barkauskas, {Donald A.} and Gorlick, {Richard G.} and Mark Purdue and Chow, {Wong Ho} and Moore, {Lee E.} and Schwartz, {Kendra L.} and Davis, {Faith G.} and Hsing, {Ann W.} and Berndt, {Sonja I.} and Amanda Black and Nicolas Wentzensen and Brinton, {Louise A.} and Jolanta Lissowska and Beata Peplonska and McGlynn, {Katherine A.} and Cook, {Michael B.} and Graubard, {Barry I.} and Kratz, {Christian P.} and Greene, {Mark H.} and Erickson, {Ralph L.} and Hunter, {David J.} and Gilles Thomas and Hoover, {Robert N.} and Real, {Francisco X.} and Fraumeni, {Joseph F.} and Caporaso, {Neil E.} and Margaret Tucker and Nathaniel Rothman and P{\'e}rez-Jurado, {Luis A.} and Chanock, {Stephen J.}",

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.",

year = "2012",

month = jun,

doi = "10.1038/ng.2270",

language = "English",

volume = "44",

pages = "651--658",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "6",

}

Jacobs, KB, Yeager, M, Zhou, W, Wacholder, S, Wang, Z, Rodriguez-Santiago, B, Hutchinson, A, Deng, X, Liu, C, Horner, MJ, Cullen, M, Epstein, CG, Burdett, L, Dean, MC, Chatterjee, N, Sampson, J, Chung, CC, Kovaks, J, Gapstur, SM, Stevens, VL, Teras, LT, Gaudet, MM, Albanes, D, Weinstein, SJ, Virtamo, J, Taylor, PR, Freedman, ND, Abnet, CC, Goldstein, AM, Hu, N, Yu, K, Yuan, JM, Liao, L, Ding, T, Qiao, YL, Gao, YT, Koh, WP, Xiang, YB, Tang, ZZ, Fan, JH, Aldrich, MC, Amos, C, Blot, WJ, Bock, CH, Gillanders, EM, Harris, CC, Haiman, CA, Henderson, BE, Kolonel, LN, Le Marchand, L, McNeill, LH, Rybicki, BA, Schwartz, AG, Signorello, LB, Spitz, MR, Wiencke, JK, Wrensch, M, Wu, X, Zanetti, KA, Ziegler, RG, Figueroa, JD, Garcia-Closas, M, Malats, N, Marenne, G, Prokunina-Olsson, L, Baris, D, Schwenn, M, Johnson, A, Landi, MT, Goldin, L, Consonni, D, Bertazzi, PA, Rotunno, M, Rajaraman, P, Andersson, U, Freeman, LEB, Berg, CD, Buring, JE, Butler, MA, Carreon, T, Feychting, M, Ahlbom, A, Gaziano, JM, Giles, GG, Hallmans, G, Hankinson, SE, Hartge, P, Henriksson, R, Inskip, PD, Johansen, C, Landgren, A, McKean-Cowdin, R, Michaud, DS, Melin, BS, Peters, U, Ruder, AM, Sesso, HD, Severi, G, Shu, XO, Visvanathan, K, White, E, Wolk, A, Zeleniuch-Jacquotte, A, Zheng, W, Silverman, DT, Kogevinas, M, Gonzalez, JR, Villa, O, Li, D, Duell, EJ, Risch, HA, Olson, SH, Kooperberg, C, Wolpin, BM, Jiao, L, Hassan, M, Wheeler, W, Arslan, AA, Bueno-De-Mesquita, HB, Fuchs, CS, Gallinger, S, Gross, MD, Holly, EA, Klein, AP, Lacroix, A, Mandelson, MT, Petersen, G, Boutron-Ruault, MC, Bracci, PM, Canzian, F, Chang, K, Cotterchio, M, Giovannucci, EL, Goggins, M, Bolton, JAH, Jenab, M, Khaw, KT, Krogh, V, Kurtz, RC, McWilliams, RR, Mendelsohn, JB, Rabe, KG, Riboli, E, Tjønneland, A, Tobias, GS, Trichopoulos, D, Elena, JW, Yu, H, Amundadottir, L, Stolzenberg-Solomon, RZ, Kraft, P, Schumacher, F, Stram, D, Savage, SA, Mirabello, L, Andrulis, IL, Wunder, JS, García, AP, SierrasesÃ maga, L, Barkauskas, DA, Gorlick, RG, Purdue, M, Chow, WH, Moore, LE, Schwartz, KL, Davis, FG, Hsing, AW, Berndt, SI, Black, A, Wentzensen, N, Brinton, LA, Lissowska, J, Peplonska, B, McGlynn, KA, Cook, MB, Graubard, BI, Kratz, CP, Greene, MH, Erickson, RL, Hunter, DJ, Thomas, G, Hoover, RN, Real, FX, Fraumeni, JF, Caporaso, NE, Tucker, M, Rothman, N, Pérez-Jurado, LA & Chanock, SJ 2012, 'Detectable clonal mosaicism and its relationship to aging and cancer', Nature Genetics, vol. 44, no. 6, pp. 651-658. https://doi.org/10.1038/ng.2270

TY - JOUR

T1 - Detectable clonal mosaicism and its relationship to aging and cancer

AU - Jacobs, Kevin B.

AU - Yeager, Meredith

AU - Zhou, Weiyin

AU - Wacholder, Sholom

AU - Wang, Zhaoming

AU - Rodriguez-Santiago, Benjamin

AU - Hutchinson, Amy

AU - Deng, Xiang

AU - Liu, Chenwei

AU - Horner, Marie Josephe

AU - Cullen, Michael

AU - Epstein, Caroline G.

AU - Burdett, Laurie

AU - Dean, Michael C.

AU - Chatterjee, Nilanjan

AU - Sampson, Joshua

AU - Chung, Charles C.

AU - Kovaks, Joseph

AU - Gapstur, Susan M.

AU - Stevens, Victoria L.

AU - Teras, Lauren T.

AU - Gaudet, Mia M.

AU - Albanes, Demetrius

AU - Weinstein, Stephanie J.

AU - Virtamo, Jarmo

AU - Taylor, Philip R.

AU - Freedman, Neal D.

AU - Abnet, Christian C.

AU - Goldstein, Alisa M.

AU - Hu, Nan

AU - Yu, Kai

AU - Yuan, Jian Min

AU - Liao, Linda

AU - Ding, Ti

AU - Qiao, You Lin

AU - Gao, Yu Tang

AU - Koh, Woon Puay

AU - Xiang, Yong Bing

AU - Tang, Ze Zhong

AU - Fan, Jin Hu

AU - Aldrich, Melinda C.

AU - Amos, Christopher

AU - Blot, William J.

AU - Bock, Cathryn H.

AU - Gillanders, Elizabeth M.

AU - Harris, Curtis C.

AU - Haiman, Christopher A.

AU - Henderson, Brian E.

AU - Kolonel, Laurence N.

AU - Le Marchand, Loic

AU - McNeill, Lorna H.

AU - Rybicki, Benjamin A.

AU - Schwartz, Ann G.

AU - Signorello, Lisa B.

AU - Spitz, Margaret R.

AU - Wiencke, John K.

AU - Wrensch, Margaret

AU - Wu, Xifeng

AU - Zanetti, Krista A.

AU - Ziegler, Regina G.

AU - Figueroa, Jonine D.

AU - Garcia-Closas, Montserrat

AU - Malats, Nuria

AU - Marenne, Gaelle

AU - Prokunina-Olsson, Ludmila

AU - Baris, Dalsu

AU - Schwenn, Molly

AU - Johnson, Alison

AU - Landi, Maria Teresa

AU - Goldin, Lynn

AU - Consonni, Dario

AU - Bertazzi, Pier Alberto

AU - Rotunno, Melissa

AU - Rajaraman, Preetha

AU - Andersson, Ulrika

AU - Freeman, Laura E.Beane

AU - Berg, Christine D.

AU - Buring, Julie E.

AU - Butler, Mary A.

AU - Carreon, Tania

AU - Feychting, Maria

AU - Ahlbom, Anders

AU - Gaziano, J. Michael

AU - Giles, Graham G.

AU - Hallmans, Goran

AU - Hankinson, Susan E.

AU - Hartge, Patricia

AU - Henriksson, Roger

AU - Inskip, Peter D.

AU - Johansen, Christoffer

AU - Landgren, Annelie

AU - McKean-Cowdin, Roberta

AU - Michaud, Dominique S.

AU - Melin, Beatrice S.

AU - Peters, Ulrike

AU - Ruder, Avima M.

AU - Sesso, Howard D.

AU - Severi, Gianluca

AU - Shu, Xiao Ou

AU - Visvanathan, Kala

AU - White, Emily

AU - Wolk, Alicja

AU - Zeleniuch-Jacquotte, Anne

AU - Zheng, Wei

AU - Silverman, Debra T.

AU - Kogevinas, Manolis

AU - Gonzalez, Juan R.

AU - Villa, Olaya

AU - Li, Donghui

AU - Duell, Eric J.

AU - Risch, Harvey A.

AU - Olson, Sara H.

AU - Kooperberg, Charles

AU - Wolpin, Brian M.

AU - Jiao, Li

AU - Hassan, Manal

AU - Wheeler, William

AU - Arslan, Alan A.

AU - Bueno-De-Mesquita, H. Bas

AU - Fuchs, Charles S.

AU - Gallinger, Steven

AU - Gross, Myron D.

AU - Holly, Elizabeth A.

AU - Klein, Alison P.

AU - Lacroix, Andrea

AU - Mandelson, Margaret T.

AU - Petersen, Gloria

AU - Boutron-Ruault, Marie Christine

AU - Bracci, Paige M.

AU - Canzian, Federico

AU - Chang, Kenneth

AU - Cotterchio, Michelle

AU - Giovannucci, Edward L.

AU - Goggins, Michael

AU - Bolton, Judith A.Hoffman

AU - Jenab, Mazda

AU - Khaw, Kay Tee

AU - Krogh, Vittorio

AU - Kurtz, Robert C.

AU - McWilliams, Robert R.

AU - Mendelsohn, Julie B.

AU - Rabe, Kari G.

AU - Riboli, Elio

AU - Tjønneland, Anne

AU - Tobias, Geoffrey S.

AU - Trichopoulos, Dimitrios

AU - Elena, Joanne W.

AU - Yu, Herbert

AU - Amundadottir, Laufey

AU - Stolzenberg-Solomon, Rachael Z.

AU - Kraft, Peter

AU - Schumacher, Fredrick

AU - Stram, Daniel

AU - Savage, Sharon A.

AU - Mirabello, Lisa

AU - Andrulis, Irene L.

AU - Wunder, Jay S.

AU - García, Ana Patiño

AU - SierrasesÃ maga, Luis

AU - Barkauskas, Donald A.

AU - Gorlick, Richard G.

AU - Purdue, Mark

AU - Chow, Wong Ho

AU - Moore, Lee E.

AU - Schwartz, Kendra L.

AU - Davis, Faith G.

AU - Hsing, Ann W.

AU - Berndt, Sonja I.

AU - Black, Amanda

AU - Wentzensen, Nicolas

AU - Brinton, Louise A.

AU - Lissowska, Jolanta

AU - Peplonska, Beata

AU - McGlynn, Katherine A.

AU - Cook, Michael B.

AU - Graubard, Barry I.

AU - Kratz, Christian P.

AU - Greene, Mark H.

AU - Erickson, Ralph L.

AU - Hunter, David J.

AU - Thomas, Gilles

AU - Hoover, Robert N.

AU - Real, Francisco X.

AU - Fraumeni, Joseph F.

AU - Caporaso, Neil E.

AU - Tucker, Margaret

AU - Rothman, Nathaniel

AU - Pérez-Jurado, Luis A.

AU - Chanock, Stephen J.

N1 - 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.

PY - 2012/6

Y1 - 2012/6

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84861628224&partnerID=8YFLogxK

U2 - 10.1038/ng.2270

DO - 10.1038/ng.2270

M3 - Article

C2 - 22561519

AN - SCOPUS:84861628224

SN - 1061-4036

VL - 44

SP - 651

EP - 658

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

Detectable clonal mosaicism and its relationship to aging and cancer

Abstract

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