Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia

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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Summary: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.

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