Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia
Abstract
The clinical and prognostic relevance of many recently identified driver gene mutations in adult acute myeloid leukemia (AML) is poorly defined. We sequenced the coding regions or hotspot areas of 68 recurrently mutated genes in a cohort of 664 patients aged 18 to 86 years treated on 2 phase 3 trials of the German AML Cooperative Group (AMLCG). The median number of 4 mutations per patient varied according to cytogenetic subgroup, age, and history of previous hematologic disorder or antineoplastic therapy. We found patterns of significantly comutated driver genes suggesting functional synergism. Conversely, we identified 8 virtually nonoverlapping patient subgroups, jointly comprising 78% of AML patients, that are defined by mutually exclusive genetic alterations. These subgroups, likely representing distinct underlying pathways of leukemogenesis, show widely divergent outcomes. Furthermore, we provide detailed information on associations between gene mutations, clinical patient characteristics, and therapeutic outcomes in this large cohort of uniformly treated AML patients. In multivariate analyses including a comprehensive set of molecular and clinical variables, we identified DNMT3A and RUNX1 mutations as important predictors of shorter overall survival (OS) in AML patients <60 years, and particularly in those with intermediate-risk cytogenetics. NPM1 mutations in the absence of FLT3-ITD, mutated TP53, and biallelic CEBPA mutations were identified as important molecular prognosticators of OS irrespective of patient age. In summary, our study provides a comprehensive overview of the spectrum, clinical associations, and prognostic relevance of recurrent driver gene mutations in a large cohort representing a broad spectrum and age range of intensively treated AML patients.
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391 out of 622 curated COSMIC cancer-related and AML-related genes were located inside altered TADs in at least one sample, and more than 100 were recurrent across multiple samples.
“We identified 391 out of the 622 curated COSMIC cancer-related and AML-related genes located inside the altered TADs in at least one sample, and more than 100 are recurrent across multiple samples (Extended Data Fig. 3b)4,24,25.”
From Subtype-specific 3D genome alteration in acute myeloid leukaemia (2022) · cites this paper as [25]
Cites
Arber, D. A., Orazi, A., Hasserjian, R., Thiele, J., Borowitz, M. J., Le Beau, M. M., Bloomfield, C. D., Cazzola, M., & Vardiman, J. W. (2016) · Blood · doi:10.1182/blood-2016-03-643544 · Cited by 10,119 · see citing works
An integrated map of genetic variation from 1,092 human genomes
The 1000 Genomes Project Consortium (2012) · Nature · doi:10.1038/nature11632 · Cited by 7,711 · see citing works
Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia
The Cancer Genome Atlas Research Network (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1301689 · Cited by 5,078 · see citing works
Genomic classification and prognosis in acute myeloid leukemia
Papaemmanuil, E., Gerstung, M., Bullinger, L., Gaidzik, V. I., Paschka, P., Roberts, N. D., Potter, N. E., Heuser, M., Thol, F., Bolli, N., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1516192 · Cited by 4,350 · see citing works
Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence
Genovese, G., Kähler, A. K., Handsaker, R. E., Lindberg, J., Rose, S. A., Bakhoum, S. F., Chambert, K., Mick, E., Neale, B. M., Fromer, M., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1409405 · Cited by 3,531 · see citing works
Döhner, H., Estey, E. H., Amadori, S., Appelbaum, F. R., Büchner, T., Burnett, A. K., Dombret, H., Fenaux, P., Grimwade, D. J., Larson, R. A., et al. (2009) · Blood · doi:10.1182/blood-2009-07-235358 · Cited by 3,348 · see citing works
Self-citationCheson, B. D., Bennett, J. M., Kopecky, K. J., Büchner, T., Willman, C. L., Estey, E. H., Schiffer, C. A., Döhner, H., Tallman, M. S., Lister, T. A., et al. (2003) · Journal of Clinical Oncology · doi:10.1200/jco.2003.04.036 · Cited by 2,686 · see citing works
Self-citationCOSMIC: exploring the world's knowledge of somatic mutations in human cancer
Forbes, S. A., Beare, D. M., Gunasekaran, P., Leung, K., Bindal, N., Boutselakis, H., Ding, M., Bamford, S., Cole, C. G., Ward, S. A., et al. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku1075 · Cited by 2,261 · see citing works
Recurring mutations found by sequencing an acute myeloid leukemia genome
Mardis, E. R., Ding, L., Dooling, D. J., Larson, D. E., McLellan, M. D., Chen, K., Koboldt, D. C., Fulton, R. S., Delehaunty, K. D., McGrath, S. D., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0903840 · Cited by 2,219 · see citing works
Creutzig, U., & Kaspers, G. J. L. (2004) · Journal of Clinical Oncology · doi:10.1200/jco.2004.99.116 · Cited by 2,137 · see citing works
<i>DNMT3A</i> Mutations in Acute Myeloid Leukemia
Ley, T. J., Ding, L., Walter, M. J., McLellan, M. D., Lamprecht, T., Larson, D. E., Kandoth, C., Payton, J. E., Baty, J., Welch, J., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa1005143 · Cited by 1,983 · see citing works
Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes
Steensma, D. P., Bejar, R., Jaiswal, S., Lindsley, R. C., Sekeres, M. A., Hasserjian, R. P., & Ebert, B. L. (2015) · Blood · doi:10.1182/blood-2015-03-631747 · Cited by 1,971 · see citing works
Prognostic Relevance of Integrated Genetic Profiling in Acute Myeloid Leukemia
Patel, J. P., Gönen, M., Figueroa, M. E., Fernandez, H. F., Sun, Z., Racevskis, J., Vlierberghe, P. V., Dolgalev, I., Thomas, S., Aminova, O., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1112304 · Cited by 1,936 · see citing works
Grimwade, D. J., Hills, R. K., Moorman, A. V., Walker, H., Chatters, S., Goldstone, A. H., Wheatley, K., Harrison, C. J., & Burnett, A. K. (2010) · Blood · doi:10.1182/blood-2009-11-254441 · Cited by 1,936 · see citing works
Clinical and biological implications of driver mutations in myelodysplastic syndromes
Papaemmanuil, E., Gerstung, M., Malcovati, L., Tauro, S., Gundem, G., Van Loo, P., Yoon, C. J., Ellis, P., Wedge, D. C., Pellagatti, A., et al. (2013) · Blood · doi:10.1182/blood-2013-08-518886 · Cited by 1,832 · see citing works
Mutations and Treatment Outcome in Cytogenetically Normal Acute Myeloid Leukemia
Schlenk, R. F., Döhner, K., Krauter, J., Fröhling, S., Corbacioglu, A., Bullinger, L., Habdank, M., Späth, D., Morgan, M., Benner, A., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa074306 · Cited by 1,628 · see citing works
Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia
Shlush, L. I., Zandi, S., Mitchell, A., Chen, W. C., Brandwein, J. M., Gupta, V., Kennedy, J. A., Schimmer, A. D., Schuh, A. C., Yee, K. W., et al. (2014) · Nature · doi:10.1038/nature13038 · Cited by 1,443 · see citing works
DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome
Ley, T. J., Mardis, E. R., Ding, L., Fulton, B., McLellan, M. D., Chen, K., Dooling, D. J., Dunford-Shore, B. H., McGrath, S. D., Hickenbotham, M. T., et al. (2008) · Nature · doi:10.1038/nature07485 · Cited by 1,415 · see citing works
Acute myeloid leukemia ontogeny is defined by distinct somatic mutations
Lindsley, R. C., Mar, B. G., Mazzola, E., Grauman, P. V., Shareef, S., Allen, S. L., Pigneux, A., Wetzler, M., Stuart, R. K., Erba, H. P., et al. (2015) · Blood · doi:10.1182/blood-2014-11-610543 · Cited by 991 · see citing works
Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia
Jan, M., Snyder, T. M., Corces-Zimmerman, M. R., Vyas, P., Weissman, I. L., Quake, S. R., & Majeti, R. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3004315 · Cited by 721 · see citing works
Rücker, F. G., Schlenk, R. F., Bullinger, L., Käyser, S., Teleanu, V., Kett, H., Habdank, M., Kugler, C.-M., Holzmann, K., Gaidzik, V. I., et al. (2011) · Blood · doi:10.1182/blood-2011-08-375758 · Cited by 680 · see citing works
Gaidzik, V. I., Bullinger, L., Schlenk, R. F., Zimmermann, A., Röck, J., Paschka, P., Corbacioglu, A., Krauter, J., Schlegelberger, B., Ganser, A., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2010.30.7926 · Cited by 454 · see citing works
Thol, F. R., Kade, S., Schlarmann, C., Löffeld, P., Morgan, M. A., Krauter, J., Włodarski, M. W., Kölking, B., Wichmann, M., Görlich, K., et al. (2012) · Blood · doi:10.1182/blood-2011-12-399337 · Cited by 420 · see citing works
Taskesen, E., Bullinger, L., Corbacioglu, A., Sanders, M. A., Erpelinck-Verschueren, C. A. J., Wouters, B. J., van der Poel, S. C. P. A. M., Damm, F., Krauter, J., Ganser, A., et al. (2010) · Blood · doi:10.1182/blood-2010-09-307280 · Cited by 384 · see citing works
Büchner, T., Berdel, W. E., Haferlach, C., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.15.4245 · Cited by 339 · see citing works
Self-citationMetzeler, K. H., Maharry, K. S., Radmacher, M. D., Mrózek, K., Margeson, D., Becker, H., Curfman, J. P., Holland, K. B., Schwind, S., Whitman, S. P., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2010.32.7742 · Cited by 316 · see citing works
Self-citationMetzeler, K. H., Becker, H., Maharry, K. S., Radmacher, M. D., Kohlschmidt, J., Mrózek, K., Nicolet, D., Whitman, S. P., Wu, Y.-Z., Schwind, S., et al. (2011) · Blood · doi:10.1182/blood-2011-08-368225 · Cited by 275 · see citing works
Self-citationClonal evolution in relapsed NPM1-mutated acute myeloid leukemia
Krönke, J., Bullinger, L., Teleanu, V., Tschürtz, F., Gaidzik, V. I., Kühn, M. W. M., Rücker, F. G., Holzmann, K., Paschka, P., Kapp‐Schwoerer, S., et al. (2013) · Blood · doi:10.1182/blood-2013-01-479188 · Cited by 272 · see citing works
Mendler, J. H., Maharry, K. S., Radmacher, M. D., Mrózek, K., Becker, H., Metzeler, K. H., Schwind, S., Whitman, S. P., Khalife, J., Kohlschmidt, J., et al. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2011.40.6652 · Cited by 268 · see citing works
Self-citationA novel hierarchical prognostic model of AML solely based on molecular mutations
Grossmann, V., Schnittger, S., Kohlmann, A., Eder, C., Roller, A., Dicker, F., Schmid, C., Wendtner, C., Staib, P., Serve, H. L., et al. (2012) · Blood · doi:10.1182/blood-2012-03-419622 · Cited by 252 · see citing works
Marcucci, G., Metzeler, K. H., Schwind, S., Becker, H., Maharry, K. S., Mrózek, K., Radmacher, M. D., Kohlschmidt, J., Nicolet, D., Whitman, S. P., et al. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2011.39.2092 · Cited by 251 · see citing works
Self-citationAcquired copy number alterations in adult acute myeloid leukemia genomes
Walter, M. J., Payton, J. E., Ries, R. E., Shannon, W. D., Deshmukh, H., Zhao, Y., Baty, J., Heath, S. E., Westervelt, P., Watson, M. A., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0903091106 · Cited by 246 · see citing works
Kihara, R., Nagata, Y., Kiyoi, H., Kato, T., Yamamoto, E., Suzuki, K., Chen, F., Asou, N., Ohtake, S., Miyawaki, S., et al. (2014) · Leukemia · doi:10.1038/leu.2014.55 · Cited by 242 · see citing works
Gaidzik, V. I., Paschka, P., Späth, D., Habdank, M., Köhne, C.-H., Germing, U., von Lilienfeld-Toal, M., Held, G., Horst, H.-A., Haase, D., et al. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2011.39.2886 · Cited by 185 · see citing works
Büchner, T., Berdel, W. E., Schoch, C., Haferlach, T., Serve, H. L., Kienast, J., Schnittger, S., Kern, W., Tchinda, J., Reichle, A., et al. (2006) · Journal of Clinical Oncology · doi:10.1200/jco.2005.04.5013 · Cited by 179 · see citing works
Self-citationGaidzik, V. I., Schlenk, R. F., Paschka, P., Stölzle, A., Späth, D., Kuendgen, A., von Lilienfeld‐Toal, M., Brugger, W., Derigs, H. G., Kremers, S., et al. (2013) · Blood · doi:10.1182/blood-2012-10-461624 · Cited by 176 · see citing works
Greif, P. A., Dufour, A. M., Konstandin, N. P., Ksienzyk, B., Zellmeier, E., Tizazu, B., Sturm, J., Benthaus, T., Herold, T., Yaghmaie, M., et al. (2012) · Blood · doi:10.1182/blood-2012-01-403220 · Cited by 149 · see citing works
Self-citationHerold, T., Metzeler, K. H., Vosberg, S., Hartmann, L., Röllig, C., Stölzel, F., Schneider, S., Hubmann, M., Zellmeier, E., Ksienzyk, B., et al. (2014) · Blood · doi:10.1182/blood-2013-12-540716 · Cited by 102 · see citing works
Self-citationGale, R. E., Lamb, K., Allen, C. G., El‐Sharkawi, D., Stowe, C., Jenkinson, S., Tinsley, S., Dickson, G. J., Burnett, A. K., Hills, R. K., et al. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2014.59.2022 · Cited by 86 · see citing works
Lavallée, V., Krošl, J., Lemieux, S., Boucher, G., Gendron, P., Pabst, C., Boivin, I., Marinier, A., Guidos, C. J., Meloche, S., et al. (2016) · Blood · doi:10.1182/blood-2016-03-705053 · Cited by 78 · see citing works
Rapid and sensitive screening for CEBPA mutations in acute myeloid leukaemia
Benthaus, T., Schneider, F., Mellert, G., et al. (2008) · British Journal of Haematology · doi:10.1111/j.1365-2141.2008.07328.x · Cited by 69 · see citing works
Schneider, F., Hoster, E., Unterhalt, M., Schneider, S., Dufour, A. M., Benthaus, T., Mellert, G., Zellmeier, E., Bohlander, S. K., Feuring‐Buske, M., et al. (2009) · Blood · doi:10.1182/blood-2008-09-172668 · Cited by 58 · see citing works
Self-citationKrug, U. O., Berdel, W. E., Gale, R. P., et al. (2016) · Leukemia · doi:10.1038/leu.2016.25 · Cited by 53 · see citing works
Self-citationWakita, S., Yamaguchi, H., Ueki, T., Usuki, K., Kurosawa, S., Kobayashi, Y., Kawata, E., Tajika, K., Gomi, S., Koizumi, M., et al. (2015) · Leukemia · doi:10.1038/leu.2015.288 · Cited by 52 · see citing works
MEGSA: A Powerful and Flexible Framework for Analyzing Mutual Exclusivity of Tumor Mutations
Hua, X., Hyland, P. L., Huang, J. L., Song, L., Zhu, B., Caporaso, N. E., Landi, M. T., Chatterjee, N., & Shi, J. (2016) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2015.12.021 · Cited by 47 · see citing works
Braess, J., Kreuzer, K., Spiekermann, K., et al. (2013) · Blood · doi:10.1182/blood.v122.21.619.619 · Cited by 10 · see citing works
Self-citationPapaemmanuil, E., Gerstung, M., Bullinger, L., Gaidzik, V. I., Paschka, P., Heuser, M., Thol, F. R., Bolli, N., Ganser, A., Döhner, K., et al. (2015) · Blood · doi:10.1182/blood.v126.23.803.803 · Cited by 5 · see citing works
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- Authors
- Metzeler, K. H., Herold, T., Rothenberg-Thurley, M., Amler, S., Sauerland, M. C., Görlich, D., Schneider, S., Konstandin, N. P., Dufour, A., Bräundl, K., Ksienzyk, B., Zellmeier, E., Hartmann, L., Greif, P. A., Fiegl, M., Subklewe, M., Bohlander, S. K., Krug, U., Faldum, A., Berdel, W. E., Wörmann, B., Büchner, T., Hiddemann, W., Braess, J., & Spiekermann, K.
- Affiliations
- German Cancer Research Center (DE)
- 1Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, Ludwig-Maximilans-Universität, Munich, Germany
- University of Münster (DE)
- Ludwig-Maximilians-Universität München (DE)
- University of Auckland (NZ)
- Klinikum Leverkusen (DE)
- 8Department of Medicine, Hematology, Oncology, Tumor Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Krankenhaus Barmherzige Brüder (DE)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2016-08-04
- Volume
- 128
- Issue
- 5
- Pages
- 686-698
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2412183643
- Cited by
- 529
- References
- 47
- Citations by year
- 2026: 22 · 2025: 42 · 2024: 35 · 2023: 49 · 2022: 60 · 2021: 72 · 2020: 71 · 2019: 67 · 2018: 54 · 2017: 43 · 2016: 11
- FWCI
- 55.44
- Type
- journal article
- Language
- en
- Update notices
- erratum (2024-08-01)
- Open access
- closed
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
- Funders
- European Hematology Association (TRTH1, CRTH1)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- acute myeloid leukemia, driver mutations, prognostic factors, DNMT3A, RUNX1, NPM1, FLT3-ITD, TP53, CEBPA, patient subgroups, overall survival, cytogenetic risk
- MeSH terms
- Nucleophosmin, Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, DNA Mutational Analysis, Female, Gene Frequency, Humans, Male, Middle Aged, Mutation, Prognosis, Risk Factors, Leukemia, Myeloid, Acute, Multivariate Analysis, Survival Analysis, Genetic Predisposition to Disease, Cytogenetic Analysis, Young Adult
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