Abstract
We determined the biological and prognostic significance of five recurrent genetic aberrations in Chinese patients with myelodysplastic syndromes (MDS). A total of 304 Chinese MDS patients were screened for known mutations in five genes (ASXL1, U2AF1, SF3B1, SRSF2, and EZH2) using next-generation sequencing. Of these, 97 patients (31.9 %) harbored at least one mutation in the five genes, and patients harboring these mutations had distinct clinical features. Incidence ratios for mutations in ASXL1, U2AF1, SF3B1, SRSF2, and EZH2 were 11.8, 8.6, 8.2, 4.3, and 3.6 %, respectively. Patients with U2AF1, SRSF2, and EZH2 mutations more commonly had high-risk than low-risk subtypes, while SF3B1 mutations were frequently confirmed in MDS subtypes with increased ring sideroblasts. Cases with ASXL1 mutations had a higher percentage of complex karyotypes, while U2AF1 mutations were more common in patients with trisomy 8 or 20q deletions. Notably, among 124 patients with a normal karyotype, 48 (38.7 %) had at least one mutation. Patients with U2AF1 or SRSF2 mutations had significantly shorter overall survival (OS) times compared with patients without these mutations (U2AF1 mutations: median OS, 18 vs 54 months, p = 0.032; SRSF2 mutations: median OS 11 vs 54 months, p = 0.005, respectively). Multivariate analysis showed that the presence of SRSF2 mutations was an independent unfavorable prognostic factor for OS (hazard ratio 2.039; 95 % confidence interval 1.040–4.000; p = 0.038). These data suggest that mutations in epigenetic modification and splicesome genes are common in Chinese patients with MDS, while mutations in U2AF1 and SRSF2 appear to predict an unfavorable prognosis.
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References
Garcia-Manero G. Myelodysplastic syndromes: 2014 update on diagnosis, risk-stratification, and management. Am J Hematol. 2014;89:97–108.
Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2079–88.
Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F, et al. Revised international prognostic scoring system (IPSS-R) for myelodysplastic syndromes. Blood. 2012;120:2454–65.
Malcovati L, Germing U, Kuendgen A, Della Porta MG, Pascutto C, Invernizzi R, et al. Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol. 2007;25:3503–10.
Itzykson R, Kosmider O, Fenaux P. Somatic mutations and epigenetic abnormalities in myelodysplastic syndromes. Best Pract Res Clin Haematol. 2013;26:355–64.
Haferlach T, Nagata Y, Grossmann V, Okuno Y, Bacher U, Nagae G, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia. 2014;28:241–7.
Gelsi-Boyer V, Trouplin V, Adélaïde J, Bonansea J, Cervera N, Carbuccia N, et al. Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Br J Haematol. 2009;145:788–800.
Thol F, Friesen I, Damm F, Yun H, Weissinger EM, Krauter J, et al. Prognostic significance of ASXL1 mutations in patients with myelodysplastic syndromes. J Clin Oncol. 2011;29:2499–506.
Nikoloski G, Langemeijer SM, Kuiper RP, Knops R, Massop M, Tönnissen ER, et al. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat Genet. 2010;42:665–7.
Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C, Jones AV, et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet. 2010;42:722–6.
Papaemmanuil E, Cazzola M, Boultwood J, Malcovati L, Vyas P, Bowen D, et al. Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N Engl J Med. 2011;365:1384–95.
Malcovati L, Papaemmanuil E, Bowen DT, Boultwood J, Della Porta MG, Pascutto C, et al. Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. Blood. 2011;118:6239–46.
Wu SJ, Kuo YY, Hou HA, Li LY, Tseng MH, Huang CF, et al. The clinical implication of SRSF2 mutation in patients with myelodysplastic syndrome and its stability during disease evolution. Blood. 2012;120:3106–11.
Thol F, Kade S, Schlarmann C, Löffeld P, Morgan M, Krauter J, et al. Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes. Blood. 2012;119:3578–84.
Graubert TA, Shen D, Ding L, Okeyo-Owuor T, Lunn CL, Shao J, et al. Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nat Genet. 2011;44:53–7.
Wang J, Ai X, Gale RP, Xu Z, Qin T, Fang L, et al. TET2, ASXL1 and EZH2 mutations in Chinese with myelodysplastic syndromes. Leuk Res. 2013;37:305–11.
Cui R, Gale RP, Xu Z, Qin T, Fang L, Zhang H, et al. Clinical importance of SF3B1 mutations in Chinese with myelodysplastic syndromes with ring sideroblasts. Leuk Res. 2012;36:1428–33.
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;114:937–51.
Malcovati L, Karimi M, Papaemmanuil E, Ambaglio I, Jädersten M, Jansson M, et al. SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts. 2015;126:233-41.
Bacher U, Haferlach T, Schnittger S, Zenger M, Meggendorfer M, Jeromin S, et al. Investigation of 305 patients with myelodysplastic syndromes and 20q deletion for associated cytogenetic and molecular genetic lesions and their prognostic impact. Br J Haematol. 2014;164:822–33.
Shirai CL, Ley JN, White BS, Kim S, Tibbitts J, Shao J, et al. Mutant U2AF1 expression alters hematopoiesis and pre-mRNA splicing in vivo. Cancer Cell. 2015;27:631–43.
Gelsi-Boyer V, Brecqueville M, Devillier R, Murati A, Mozziconacci MJ, Birnbaum D. Mutations in ASXL1 are associated with poor prognosis across the spectrum of malignant myeloid diseases. J Hematol Oncol. 2012;5:12.
Chen TC, Hou HA, Chou WC, Tang JL, Kuo YY, Chen CY, et al. Dynamics of ASXL1 mutation and other associated genetic alterations during disease progression in patients with primary myelodysplastic syndrome. Blood Cancer J. 2014;4:e177.
Patnaik MM, Lasho TL, Hodnefield JM, Knudson RA, Ketterling RP, Garcia-Manero G, et al. SF3B1 mutations are prevalent in myelodysplastic syndromes with ring sideroblasts but do not hold independent prognostic value. Blood. 2012;119:569–72.
Damm F, Thol F, Kosmider O, Kade S, Löffeld P, Dreyfus F, et al. SF3B1 mutations in myelodysplastic syndromes: clinical associations and prognostic implications. Leukemia. 2012;26:1137–40.
Xiao R, Sun Y, Ding JH, Lin S, Rose DW, Rosenfeld MG, et al. Splicing regulator SC35 is essential for genomic stability and cell proliferation during mammalian organogenesis. Mol Cell Biol. 2007;27:5393–402.
Heilig CE, Löffler H, Mahlknecht U, Janssen JW, Ho AD, Jauch A, et al. Chromosomal instability correlates with poor outcome in patients with myelodysplastic syndromes irrespectively of the cytogenetic risk group. J Cell Mol Med. 2010;14:895–902.
Katoh M. Functional and cancer genomics of ASXL family members. Br J Cancer. 2013;109:299–306.
Inoue D, Kitaura J, Togami K, Nishimura K, Enomoto Y, Uchida T, et al. Myelodysplastic syndromes are induced by histone methylation-altering ASXL1 mutations. J Clin Invest. 2013;123:4627–40.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.
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This study was funded by the National Science Foundation of China (grant numbers 81270584 and 81200346).
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Saijuan Chen and Xiao Li contributed equally to this work.
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Wu, L., Song, L., Xu, L. et al. Genetic landscape of recurrent ASXL1, U2AF1, SF3B1, SRSF2, and EZH2 mutations in 304 Chinese patients with myelodysplastic syndromes. Tumor Biol. 37, 4633–4640 (2016). https://doi.org/10.1007/s13277-015-4305-2
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DOI: https://doi.org/10.1007/s13277-015-4305-2