Detectable clonal mosaicism and its relationship to aging and cancer

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

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Christian Abnet
Jacobs et al., 2012

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Nature Research, Nature Genetics, 6(44), p. 651-658, 2012

DOI: 10.1038/ng.2270

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@article{Jacobs2012,
  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 &gt;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 Yeager, Meredith and Kb, Jacobs and Zhou, Weiyin and Wacholder, Sholom and Wang, Zhaoming and Rodriguez-Santiago, Benjamin and Hutchinson, Amy and Deng, Xiang and Liu, Chenwei and Horner, Marie-Josephe and Cullen, Michael and Epstein, Caroline G. and Burdett, Laurie and Dean, Michael C. and Chatterjee, Nilanjan and Sampson, Joshua and Chung, Charles C. and Kovaks, Joseph and Gapstur, Susan M. and Stevens, Victoria L. and Teras, Lauren T. and Gaudet, Mia M. and Albanes, Demetrius and Weinstein, Stephanie J. and Virtamo, Jarmo and Taylor, Philip R. and Freedman, Neal D. and Abnet, Christian C. and Goldstein, Alisa M. and Hu, Nan and Yu, Kai and Yuan, Jian-Min and Liao, Linda and Ding, Ti 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 Amos, Christopher and Blot, William J. and Bock, Cathryn H. and Gillanders, Elizabeth M. and Harris, Curtis C. and Haiman, Christopher A. and Mj, Horner 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 Wrensch, Margaret and Wu, Xifeng and Zanetti, Krista A. and Ziegler, Regina G. and Figueroa, Jonine D. and Garcia-Closas, Montserrat and Cg, Epstein and Malats, Nuria and Marenne, Gaelle and Prokunina-Olsson, Ludmila and Baris, Dalsu and Schwenn, Molly and Johnson, Alison and Landi, Maria Teresa and Goldin, Lynn and Consonni, Dario and Bertazzi, Pier Alberto and Rotunno, Melissa and Rajaraman, Preetha and Andersson, Ulrika and Freeman, Laura E. Beane and Berg, Christine D. and Buring, Julie E. and Mc, Dean and Butler, Mary A. and Carreon, Tania and Feychting, Maria and Ahlbom, Anders and Gaziano, J. Michael and Giles, Graham G. and Hallmans, Goran and Hankinson, Susan E. and Hartge, Patricia and Henriksson, Roger and Inskip, Peter D. and Johansen, Christoffer and Landgren, Annelie and McKean-Cowdin, Roberta and Michaud, Dominique S. and Melin, Beatrice S. and Peters, Ulrike and Ruder, Avima M. and Sesso, Howard D. and Severi, Gianluca and Shu, Xiao-Ou and Visvanathan, Kala and White, Emily and Cc, Chung and Wolk, Alicja and Zeleniuch-Jacquotte, Anne and Zheng, Wei and Silverman, Debra T. and Kogevinas, Manolis and Gonzalez, Juan R. and Villa, Olaya and Li, Donghui and Duell, Eric J. and Risch, Harvey A. and Olson, Sara H. and Kooperberg, Charles and Wolpin, Brian M. and Jiao, Li and Hassan, Manal and Sm, Gapstur and Wheeler, William and Arslan, Alan A. and Bueno-De-Mesquita, H. Bas and Fuchs, Charles S. and Gallinger, Steven and Gross, Myron D. and Holly, Elizabeth A. and Klein, Alison P. and LaCroix, Andrea and Mandelson, Margaret T. and Vl, Stevens and Petersen, Gloria and Boutron-Ruault, Marie-Christine and Bracci, Paige M. and Canzian, Federico and Chang, Kenneth and Cotterchio, Michelle and Giovannucci, Edward L. and Goggins, Michael and Bolton, Judith A. Hoffman and Jenab, Mazda and Khaw, Kay-Tee and Krogh, Vittorio and Kurtz, Robert C. and McWilliams, Robert R. and Mendelsohn, Julie B. and Rabe, Kari G. and Riboli, Elio and Tjonneland, Anne and Tobias, Geoffrey S. and Patino Garcia, Ana and Trichopoulos, Dimitrios and Elena, Joanne W. and Yu, Herbert and Amundadottir, Laufey and Stolzenberg-Solomon, Rachael Z. and Kraft, Peter and Schumacher, Fredrick and Stram, Daniel and Savage, Sharon A. and Mirabello, Lisa and Andrulis, Irene L. and Wunder, Jay S. and Lt, Teras and García, Ana Patiño and Sierrasesumaga, Luis and Barkauskas, Donald A. and Gorlick, Richard G. and Purdue, Mark and Chow, Wong-Ho and Moore, Lee E. and Schwartz, Kendra L. and Mm, Gaudet and Davis, Faith G. and Hsing, Ann W. and Berndt, Sonja I. and Black, Amanda and Wentzensen, Nicolas and Brinton, Louise A. and Lissowska, Jolanta and Peplonska, Beata 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 Sj, Weinstein and Thomas, Gilles and Hoover, Robert N. and Real, Francisco X. and Fraumeni, Joseph F. and Caporaso, Neil E. and Tucker, Margaret and Rothman, Nathaniel and Pérez-Jurado, Luis A. and Perez-Jurado, Luis A. and Chanock, Stephen J.},
  doi = {10.1038/ng.2270},
  journal = {Nature Genetics},
  month = {may},
  pages = {651-658},
  title = {Detectable clonal mosaicism and its relationship to aging and cancer},
  url = {http://www.nature.com/articles/ng.2270.pdf},
  volume = {44},
  year = {2012}
}

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Detectable clonal mosaicism and its relationship to aging and cancer

Journal article published in 2012 by Kevin B. Jacobs, Meredith Yeager, Jacobs Kb, 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 and other authors. Kevin B. Jacobs, Meredith Yeager, Jacobs Kb, 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, Horner Mj, 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, Epstein Cg, 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, Dean Mc, 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, Chung Cc, 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, Gapstur Sm, 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, Stevens Vl, 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 Tjonneland, Geoffrey S. Tobias

, Ana Patino Garcia, 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, Teras Lt, Ana Patiño García, Luis Sierrasesumaga, Donald A. Barkauskas, Richard G. Gorlick, Mark Purdue, Wong-Ho Chow, Lee E. Moore, Kendra L. Schwartz, Gaudet Mm, 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, Weinstein Sj, Gilles Thomas, Robert N. Hoover, Francisco X. Real

, Joseph F. Fraumeni, Neil E. Caporaso, Margaret Tucker, Nathaniel Rothman, Luis A. Pérez-Jurado, Luis A. Perez-Jurado, Stephen J. Chanock

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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.

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Detectable clonal mosaicism and its relationship to aging and cancer

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