Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia

BACKGROUND: Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined. The relationships between patterns of mutations and epigenetic phenotypes are not yet clear. METHODS: We analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using ei...

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Main Authors:	Ley, T., Miller, C., Ding, L., Raphael, B., Mungall, A., Robertson, G., Hoadley, K., Triche, T., Laird, P., Baty, J., Fulton, L., Fulton, R., Heath, S., Kalicki-Veizer, J., Kandoth, C., Klco, J., Koboldt, D., Kanchi, K., Kulkarni, S., Lamprecht, T., Larson, D., Lin, G., Lu, C., McLellan, M., McMichael, J., Payton, J., Schmidt, H., Spencer, D., Tomasson, M., Wallis, J., Wartman, L., Watson, M., Welch, J., Wendl, M., Ally, A., Balasundaram, M., Birol, I., Butterfield, Y., Chiu, R., Chu, A., Chuah, E., Chun, H., Corbett, R., Dhalla, N., Guin, R., He, A., Hirst, C., Hirst, M., Holt, R., Jones, S., Karsan, A., Lee, D., Li, H., Marra, M., Mayo, M., Moore, R., Mungall, K., Parker, J., Pleasance, E., Plettner, P., Schein, J., Stoll, D., Swanson, L., Tam, A., Thiessen, N., Varhol, Richard, Wye, N., Zhao, Y., Gabriel, S., Getz, G., Sougnez, C., Zou, L., Leiserson, M., Vandin, F., Wu, H., Applebaum, F., Baylin, S., Akbani, R., Broom, B., Chen, K., Motter, T., Nguyen, K., Weinstein, J., Zhang, N., Ferguson, M., Adams, C., Black, A., Bowen, J., Gastier-Foster, J., Grossman, T., Lichtenberg, T., Wise, L., Davidsen, T., Demchok, J., Mills Shaw, K., Sheth, M., Sofia, H., Yang, L., Downing, J., Eley, G.
Format:	Journal Article
Published:	2013
Online Access:	http://hdl.handle.net/20.500.11937/38906

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author	Ley, T. Miller, C. Ding, L. Raphael, B. Mungall, A. Robertson, G. Hoadley, K. Triche, T. Laird, P. Baty, J. Fulton, L. Fulton, R. Heath, S. Kalicki-Veizer, J. Kandoth, C. Klco, J. Koboldt, D. Kanchi, K. Kulkarni, S. Lamprecht, T. Larson, D. Lin, G. Lu, C. McLellan, M. McMichael, J. Payton, J. Schmidt, H. Spencer, D. Tomasson, M. Wallis, J. Wartman, L. Watson, M. Welch, J. Wendl, M. Ally, A. Balasundaram, M. Birol, I. Butterfield, Y. Chiu, R. Chu, A. Chuah, E. Chun, H. Corbett, R. Dhalla, N. Guin, R. He, A. Hirst, C. Hirst, M. Holt, R. Jones, S. Karsan, A. Lee, D. Li, H. Marra, M. Mayo, M. Moore, R. Mungall, K. Parker, J. Pleasance, E. Plettner, P. Schein, J. Stoll, D. Swanson, L. Tam, A. Thiessen, N. Varhol, Richard Wye, N. Zhao, Y. Gabriel, S. Getz, G. Sougnez, C. Zou, L. Leiserson, M. Vandin, F. Wu, H. Applebaum, F. Baylin, S. Akbani, R. Broom, B. Chen, K. Motter, T. Nguyen, K. Weinstein, J. Zhang, N. Ferguson, M. Adams, C. Black, A. Bowen, J. Gastier-Foster, J. Grossman, T. Lichtenberg, T. Wise, L. Davidsen, T. Demchok, J. Mills Shaw, K. Sheth, M. Sofia, H. Yang, L. Downing, J. Eley, G.
author_facet	Ley, T. Miller, C. Ding, L. Raphael, B. Mungall, A. Robertson, G. Hoadley, K. Triche, T. Laird, P. Baty, J. Fulton, L. Fulton, R. Heath, S. Kalicki-Veizer, J. Kandoth, C. Klco, J. Koboldt, D. Kanchi, K. Kulkarni, S. Lamprecht, T. Larson, D. Lin, G. Lu, C. McLellan, M. McMichael, J. Payton, J. Schmidt, H. Spencer, D. Tomasson, M. Wallis, J. Wartman, L. Watson, M. Welch, J. Wendl, M. Ally, A. Balasundaram, M. Birol, I. Butterfield, Y. Chiu, R. Chu, A. Chuah, E. Chun, H. Corbett, R. Dhalla, N. Guin, R. He, A. Hirst, C. Hirst, M. Holt, R. Jones, S. Karsan, A. Lee, D. Li, H. Marra, M. Mayo, M. Moore, R. Mungall, K. Parker, J. Pleasance, E. Plettner, P. Schein, J. Stoll, D. Swanson, L. Tam, A. Thiessen, N. Varhol, Richard Wye, N. Zhao, Y. Gabriel, S. Getz, G. Sougnez, C. Zou, L. Leiserson, M. Vandin, F. Wu, H. Applebaum, F. Baylin, S. Akbani, R. Broom, B. Chen, K. Motter, T. Nguyen, K. Weinstein, J. Zhang, N. Ferguson, M. Adams, C. Black, A. Bowen, J. Gastier-Foster, J. Grossman, T. Lichtenberg, T. Wise, L. Davidsen, T. Demchok, J. Mills Shaw, K. Sheth, M. Sofia, H. Yang, L. Downing, J. Eley, G.
author_sort	Ley, T.
building	Curtin Institutional Repository
collection	Online Access
description	BACKGROUND: Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined. The relationships between patterns of mutations and epigenetic phenotypes are not yet clear. METHODS: We analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA-methylation analysis. RESULTS: AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations found in genes. Of these, an average of 5 are in genes that are recurrently mutated in AML. A total of 23 genes were significantly mutated, and another 237 were mutated in two or more samples. Nearly all samples had at least 1 nonsynonymous mutation in one of nine categories of genes that are almost certainly relevant for pathogenesis, including transcription-factor fusions (18% of cases), the gene encoding nucleophosmin (NPM1) (27%), tumor-suppressor genes (16%), DNA-methylation-related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%). Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories. CONCLUSIONS: We identified at least one potential driver mutation in nearly all AML samples and found that a complex interplay of genetic events contributes to AML pathogenesis in individual patients. The databases from this study are widely available to serve as a foundation for further investigations of AML pathogenesis, classification, and risk stratification. (Funded by the National Institutes of Health.) Copyright © 2013 Massachusetts Medical Society.
first_indexed	2025-11-14T08:56:26Z
format	Journal Article
id	curtin-20.500.11937-38906
institution	Curtin University Malaysia
institution_category	Local University
last_indexed	2025-11-14T08:56:26Z
publishDate	2013
recordtype	eprints
repository_type	Digital Repository
spelling	curtin-20.500.11937-389062018-03-29T09:07:33Z Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia Ley, T. Miller, C. Ding, L. Raphael, B. Mungall, A. Robertson, G. Hoadley, K. Triche, T. Laird, P. Baty, J. Fulton, L. Fulton, R. Heath, S. Kalicki-Veizer, J. Kandoth, C. Klco, J. Koboldt, D. Kanchi, K. Kulkarni, S. Lamprecht, T. Larson, D. Lin, G. Lu, C. McLellan, M. McMichael, J. Payton, J. Schmidt, H. Spencer, D. Tomasson, M. Wallis, J. Wartman, L. Watson, M. Welch, J. Wendl, M. Ally, A. Balasundaram, M. Birol, I. Butterfield, Y. Chiu, R. Chu, A. Chuah, E. Chun, H. Corbett, R. Dhalla, N. Guin, R. He, A. Hirst, C. Hirst, M. Holt, R. Jones, S. Karsan, A. Lee, D. Li, H. Marra, M. Mayo, M. Moore, R. Mungall, K. Parker, J. Pleasance, E. Plettner, P. Schein, J. Stoll, D. Swanson, L. Tam, A. Thiessen, N. Varhol, Richard Wye, N. Zhao, Y. Gabriel, S. Getz, G. Sougnez, C. Zou, L. Leiserson, M. Vandin, F. Wu, H. Applebaum, F. Baylin, S. Akbani, R. Broom, B. Chen, K. Motter, T. Nguyen, K. Weinstein, J. Zhang, N. Ferguson, M. Adams, C. Black, A. Bowen, J. Gastier-Foster, J. Grossman, T. Lichtenberg, T. Wise, L. Davidsen, T. Demchok, J. Mills Shaw, K. Sheth, M. Sofia, H. Yang, L. Downing, J. Eley, G. BACKGROUND: Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined. The relationships between patterns of mutations and epigenetic phenotypes are not yet clear. METHODS: We analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA-methylation analysis. RESULTS: AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations found in genes. Of these, an average of 5 are in genes that are recurrently mutated in AML. A total of 23 genes were significantly mutated, and another 237 were mutated in two or more samples. Nearly all samples had at least 1 nonsynonymous mutation in one of nine categories of genes that are almost certainly relevant for pathogenesis, including transcription-factor fusions (18% of cases), the gene encoding nucleophosmin (NPM1) (27%), tumor-suppressor genes (16%), DNA-methylation-related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%). Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories. CONCLUSIONS: We identified at least one potential driver mutation in nearly all AML samples and found that a complex interplay of genetic events contributes to AML pathogenesis in individual patients. The databases from this study are widely available to serve as a foundation for further investigations of AML pathogenesis, classification, and risk stratification. (Funded by the National Institutes of Health.) Copyright © 2013 Massachusetts Medical Society. 2013 Journal Article http://hdl.handle.net/20.500.11937/38906 10.1056/NEJMoa1301689 restricted
spellingShingle	Ley, T. Miller, C. Ding, L. Raphael, B. Mungall, A. Robertson, G. Hoadley, K. Triche, T. Laird, P. Baty, J. Fulton, L. Fulton, R. Heath, S. Kalicki-Veizer, J. Kandoth, C. Klco, J. Koboldt, D. Kanchi, K. Kulkarni, S. Lamprecht, T. Larson, D. Lin, G. Lu, C. McLellan, M. McMichael, J. Payton, J. Schmidt, H. Spencer, D. Tomasson, M. Wallis, J. Wartman, L. Watson, M. Welch, J. Wendl, M. Ally, A. Balasundaram, M. Birol, I. Butterfield, Y. Chiu, R. Chu, A. Chuah, E. Chun, H. Corbett, R. Dhalla, N. Guin, R. He, A. Hirst, C. Hirst, M. Holt, R. Jones, S. Karsan, A. Lee, D. Li, H. Marra, M. Mayo, M. Moore, R. Mungall, K. Parker, J. Pleasance, E. Plettner, P. Schein, J. Stoll, D. Swanson, L. Tam, A. Thiessen, N. Varhol, Richard Wye, N. Zhao, Y. Gabriel, S. Getz, G. Sougnez, C. Zou, L. Leiserson, M. Vandin, F. Wu, H. Applebaum, F. Baylin, S. Akbani, R. Broom, B. Chen, K. Motter, T. Nguyen, K. Weinstein, J. Zhang, N. Ferguson, M. Adams, C. Black, A. Bowen, J. Gastier-Foster, J. Grossman, T. Lichtenberg, T. Wise, L. Davidsen, T. Demchok, J. Mills Shaw, K. Sheth, M. Sofia, H. Yang, L. Downing, J. Eley, G. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia
title	Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia
title_full	Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia
title_fullStr	Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia
title_full_unstemmed	Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia
title_short	Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia
title_sort	genomic and epigenomic landscapes of adult de novo acute myeloid leukemia
url	http://hdl.handle.net/20.500.11937/38906

Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia

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