Abstract
To clarify the cooperative roles of recurrently identified mutations and to establish a more precise risk classification system in acute myeloid leukemia (AML), we comprehensively analyzed mutations in 51 genes, as well as cytogenetics and 11 chimeric transcripts, in 197 adult patients with de novo AML who were registered in the Japan Adult Leukemia Study Group AML201 study. We identified a total of 505 mutations in 44 genes, while only five genes, FLT3, NPM1, CEBPA, DNMT3A and KIT, were mutated in more than 10% of the patients. Although several cooperative and exclusive mutation patterns were observed, the accumulated mutation number was higher in cytogenetically normal AML and lower in AML with RUNX1-RUNX1T1 and CBFB-MYH11, indicating a strong potential of these translocations for the initiation of AML. Furthermore, we evaluated the prognostic impacts of each sole mutation and the combinations of mutations and/or cytogenetics, and demonstrated that AML patients could be clearly stratified into five risk groups for overall survival by including the mutation status of DNMT3A, MLL-PTD and TP53 genes in the risk classification system of the European LeukemiaNet. These results indicate that the prognosis of AML could be stratified by the major mutation status in combination with cytogenetics.
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References
Estey E, Dohner H . Acute myeloid leukaemia. Lancet 2006; 368: 1894–1907.
Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010; 115: 453–474.
Koreth J, Schlenk R, Kopecky KJ, Honda S, Sierra J, Djulbegovic BJ et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA 2009; 301: 2349–2361.
Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 2010; 116: 354–365.
Patel JP, Gonen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012; 366: 1079–1089.
Shen Y, Zhu YM, Fan X, Shi JY, Wang QR, Yan XJ et al. Gene mutation patterns and their prognostic impact in a cohort of 1185 patients with acute myeloid leukemia. Blood 2011; 118: 5593–5603.
Ofran Y, Rowe JM . Genetic profiling in acute myeloid leukaemia—where are we and what is its role in patient management. Br J Haematol 2013; 160: 303–320.
Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Masse A et al. Mutation in TET2 in myeloid cancers. N Engl J Med 2009; 360: 2289–2301.
Langemeijer SM, Kuiper RP, Berends M, Knops R, Aslanyan MG, Massop M et al. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet 2009; 41: 838–842.
Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 2009; 361: 1058–1066.
Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med 2010; 363: 2424–2433.
Nikoloski G, Langemeijer SM, Kuiper RP, Knops R, Massop M, Tonnissen ER et al. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat Genet 2010; 42: 665–667.
Shih AH, Abdel-Wahab O, Patel JP, Levine RL . The role of mutations in epigenetic regulators in myeloid malignancies. Nat Rev Cancer 2012; 12: 599–612.
Chou WC, Huang HH, Hou HA, Chen CY, Tang JL, Yao M et al. Distinct clinical and biological features of de novo acute myeloid leukemia with additional sex comb-like 1 (ASXL1) mutations. Blood 2010; 116: 4086–4094.
Grossmann V, Tiacci E, Holmes AB, Kohlmann A, Martelli MP, Kern W et al. Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype. Blood 2011; 118: 6153–6163.
Li M, Collins R, Jiao Y, Ouillette P, Bixby D, Erba H et al. Somatic mutations in the transcriptional corepressor gene BCORL1 in adult acute myelogenous leukemia. Blood 2011; 118: 5914–5917.
Welch JS, Ley TJ, Link DC, Miller CA, Larson DE, Koboldt DC et al. The origin and evolution of mutations in acute myeloid leukemia. Cell 2012; 150: 264–278.
Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 2011; 478: 64–69.
Naoe T, Kiyoi H . Gene mutations of acute myeloid leukemia in the genome era. Int J Hematol 2013; 97: 165–174.
Rollig C, Bornhauser M, Thiede C, Taube F, Kramer M, Mohr B et al. Long-term prognosis of acute myeloid leukemia according to the new genetic risk classification of the European LeukemiaNet recommendations: evaluation of the proposed reporting system. J Clin Oncol 2011; 29: 2758–2765.
Mrozek K, Marcucci G, Nicolet D, Maharry KS, Becker H, Whitman SP et al. Prognostic significance of the European LeukemiaNet standardized system for reporting cytogenetic and molecular alterations in adults with acute myeloid leukemia. J Clin Oncol 2012; 30: 4515–4523.
Metzeler KH, Maharry K, Radmacher MD, Mrozek K, Margeson D, Becker H et al. TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol 2011; 29: 1373–1381.
Miyawaki S . Clinical studies of acute myeloid leukemia in the Japan Adult Leukemia Study Group. Int J Hematol 2012; 96: 171–177.
Ohtake S, Miyawaki S, Fujita H, Kiyoi H, Shinagawa K, Usui N et al. Randomized study of induction therapy comparing standard-dose idarubicin with high-dose daunorubicin in adult patients with previously untreated acute myeloid leukemia: the JALSG AML201 Study. Blood 2011; 117: 2358–2365.
Miyawaki S, Ohtake S, Fujisawa S, Kiyoi H, Shinagawa K, Usui N et al. A randomized comparison of 4 courses of standard-dose multiagent chemotherapy versus 3 courses of high-dose cytarabine alone in postremission therapy for acute myeloid leukemia in adults: the JALSG AML201 Study. Blood 2011; 117: 2366–2372.
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR et al. Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann Intern Med 1985; 103: 620–625.
Kiyoi H, Naoe T, Nakano Y, Yokota S, Minami S, Miyawaki S et al. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood 1999; 93: 3074–3080.
Ozeki K, Kiyoi H, Hirose Y, Iwai M, Ninomiya M, Kodera Y et al. Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia. Blood 2004; 103: 1901–1908.
Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 2001; 97: 2434–2439.
Osumi K, Fukui T, Kiyoi H, Kasai M, Kodera Y, Kudo K et al. Rapid screening of leukemia fusion transcripts in acute leukemia by real-time PCR. Leuk Lymphoma 2002; 43: 2291–2299.
Makishima H, Yoshida K, Nguyen N, Przychodzen B, Sanada M, Okuno Y et al. Somatic SETBP1 mutations in myeloid malignancies. Nat Genet 2013; 45: 942–946.
Kon A, Shih LY, Minamino M, Sanada M, Shiraishi Y, Nagata Y et al. Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms. Nat Genet 2013; 45: 1232–1237.
Sakaguchi H, Okuno Y, Muramatsu H, Yoshida K, Shiraishi Y, Takahashi M et al. Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. Nat Genet 2013; 45: 937–941.
Ishikawa Y, Kiyoi H, Tsujimura A, Miyawaki S, Miyazaki Y, Kuriyama K et al. Comprehensive analysis of cooperative gene mutations between class I and class II in de novo acute myeloid leukemia. Eur J Haematol 2009; 83: 90–98.
Speck NA, Gilliland DG . Core-binding factors in haematopoiesis and leukaemia. Nat Rev Cancer 2002; 2: 502–513.
Swerdlow S, Campo E, Harris N, Jaffe E, Pileri S, Stein H et al WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 4th edn. WHO Press: Lyon, 2008.
Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009; 114: 937–951.
Abdel-Wahab O, Levine RL . Mutations in epigenetic modifiers in the pathogenesis and therapy of acute myeloid leukemia. Blood 2013; 121: 3563–3572.
Grossmann V, Schnittger S, Kohlmann A, Eder C, Roller A, Dicker F et al. A novel hierarchical prognostic model of AML solely based on molecular mutations. Blood 2012; 120: 2963–2972.
Cancer Genome Atlas Research N. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013; 368: 2059–2074.
Tang JL, Hou HA, Chen CY, Liu CY, Chou WC, Tseng MH et al. AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations. Blood 2009; 114: 5352–5361.
Stone RM . Acute myeloid leukemia in first remission: to choose transplantation or not? J Clin Oncol 2013; 31: 1262–1266.
Paschka P, Schlenk RF, Gaidzik VI, Habdank M, Kronke J, Bullinger L et al. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol 2010; 28: 3636–3643.
Dufour A, Schneider F, Metzeler KH, Hoster E, Schneider S, Zellmeier E et al. Acute myeloid leukemia with biallelic CEBPA gene mutations and normal karyotype represents a distinct genetic entity associated with a favorable clinical outcome. J Clin Oncol 2010; 28: 570–577.
Krzywinski M, Schein J, Birol I, Connors J, Gascoyne R, Horsman D et al. Circos: an information aesthetic for comparative genomics. Genome Res 2009; 19: 1639–1645.
Acknowledgements
This study was performed as a research program of the Project for Development of Innovative Research on Cancer Therapeutics (P-Direct), Ministry of Education, Culture, Sports, Science and Technology of Japan, and was also supported by Grants-in-Aid from the Scientific Research Program from the Japanese Ministry of Education, Culture, Sports, Science, and Technology, the Ministry of Health, Labor and Welfare for Cancer Research (Clinical Cancer Research H23-004 and H25-006), the National Cancer Center Research and Development Fund (23-A-23) and from KAKENHI (22134006 and 23249052).
Author contributions
H Kiyoi, S Ogawa and TN designed the study, interpreted the data and wrote the manuscript; RK, YN, T Kato, EY, KS and FC performed molecular analysis and interpreted the data; YN, YS, KC, HT, SM and S Ogawa performed bioinformatics; NA, S Ohtake, SM, YM, TS, YO, N Usui, H Kanamori, T Kiguchi, KI, N Uike, FK, KK, CN, MO, AT, FI, HS, YK and HM collected samples and clinical data, contributed to the interpretation of the data and critically reviewed the draft; and all authors approved the final version submitted for the publication.
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H Kiyoi: Research funding from Bristol-Myers Squibb, Novartis Pharma, Chugai Pharmaceutical Co., Ltd. and Kyowa Hakko Kirin Co., Ltd. YM: Honoraria from Bristol-Myers Squibb, Novartis Pharma, Chugai Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd. and Celgene Japan; Research funding from Bristol-Myers Squibb, Novartis Pharma, Chugai Pharmaceutical Co., Ltd. and Kyowa Hakko Kirin Co., Ltd. NU: Consultant for Kyowa Hakko Kirin Co., Ltd.; Honoraria from Bristol-Myers Squibb, Novartis Pharma and Chugai Pharmaceutical Co., Ltd.; Research funding from Bristol-Myers Squibb, Novartis Pharma, Chugai Pharmaceutical Co., Ltd. and Kyowa Hakko Kirin Co., Ltd. TN: Research funding from Bristol-Myers Squibb, Novartis Pharma, Chugai Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Dainippon Sumitomo Pharma and Zenyaku Kogyo. The other authors declare no conflict of interest.
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Kihara, R., Nagata, Y., Kiyoi, H. et al. Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients. Leukemia 28, 1586–1595 (2014). https://doi.org/10.1038/leu.2014.55
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DOI: https://doi.org/10.1038/leu.2014.55
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