TET2 mutation is an independent favorable prognostic factor in myelodysplastic syndromes (MDSs)

Kosmider, Olivier; Gelsi‐Boyer, Véronique; Cheok, Meyling; Grabar, Sophie; Della-Valle, Véronique; Picard, Françoise; Viguié, F; Quesnel, Bruno; Beyne‐Rauzy, Odile; Solary, Éric; Vey, Norbert; Hunault, Mathilde; Fenaux, Pierre; Mas, Véronique Mansat‐De; Delabesse, Éric; Guardiola, Philippe; Lacombe, Catherine; Vainchenker, William; Preudhomme, Claude; Dreyfus, François; Bernard, Olivier A.; Birnbaum, Daniel; Fontenay, Michaëla

doi:10.1182/blood-2009-04-215814

Cited by 254 publications

(198 citation statements)

References 31 publications

(38 reference statements)

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“…Although TET2 was identified as the most frequently mutated gene in MDS, [18][19][20] its role in disease remains controversial; two reports describe no impact of TET2 mutations on survival in MDS/MPD (myeloproliferative disease), 18,21 another describes an association with decreased overall survival in AML 13 and, most recently, TET2 mutations were reported to be an independent favorable prognostic factor in MDS. 22 Two patients had submicroscopic deletions in 5q; one was only 1.35 Mb in 5q31.2, affecting the more proximal AML/MDS region. The deletion includes all candidate ts genes described so far in this region: CTNNA, 23 EGR1 24 and HSPA9, which shows increased expression during EPO-induced erythroid differentiation.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive array CGH of normal karyotype myelodysplastic syndromes reveals hidden recurrent and individual genomic copy number alterations with prognostic relevance

et al. 2011

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About 40% of patients with myelodysplastic syndromes (MDSs) present with a normal karyotype, and they are facing different courses of disease. To advance the biological understanding and to find molecular prognostic markers, we performed a highresolution oligonucleotide array study of 107 MDS patients (French American British) with a normal karyotype and clinical follow-up through the Duesseldorf MDS registry. Recurrent hidden deletions overlapping with known cytogenetic aberrations or sites of known tumor-associated genes were identified in 4q24 (TET2, 2x), 5q31.2 (2x), 7q22.1 (3x) and 21q22.12 (RUNX1, 2x). One patient with a 7q22.1 deletion had an additional 5q31.2 deletion of the acute myeloid leukemia/MDS region, the smallest deletion identified so far and including the putative tumor suppressor (ts) genes, EGR1 and CTNNA1. One TET2 deletion was homozygous and one heterozygous, with a missense mutation in the remaining allele, further supporting its role as a ts gene. Besides these recurrent alterations, additional individual imbalances were found in 34 cases; in total, 42/107 (39%) cases had genomic imbalances. These patients had an inferior survival as compared with the rest of the patients (P ¼ 0.002). This study emphasizes the heterogeneity of MDS, but points to interesting genes that may have diagnostic and prognostic impact.

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Section: Discussionmentioning

confidence: 99%

Comprehensive array CGH of normal karyotype myelodysplastic syndromes reveals hidden recurrent and individual genomic copy number alterations with prognostic relevance

et al. 2011

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“…There was a trend towards shorter survival for mutated cases that was significant for the relatively small group of CMML-1 cases: clearly this needs to be independently verified and is perhaps surprising in view of the same group's recent finding that TET2 mutations are a favorable prognostic factor in MDS. 19 Of interest, the association of TET2 mutation and monocytosis was also found in patients with systemic mastocytosis, 20 sug- with regard to pathogenesis and 3) no arrangement of PDGFRA or PDGFRB (particularly, in cases with eosinophilia); prognosis) 4) fewer than 20% blasts in the peripheral blood and the bone marrow; 5) at least one of the following: i) dysplasia in one or more cell lines; ii) clonal cytogenetic TET2 mutations in up to 40% of patients abnormality or somatic mutation in myeloid cells; iii) persistence of monocytosis for at least three months with the exclusion of any other cause for this hematologic abnormality.…”

Section: Molecular Basis Of Myelodysplastic/myeloproliferative Neoplasmsmentioning

confidence: 99%

Molecular basis of myelodysplastic/myeloproliferative neoplasms

Reiter

Invernizzi²,

Cross³

et al. 2009

Haematologica

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“…[8][9][10][11][12] Acquired somatic mutations of TET2 have been detected in different myeloid neoplasms and in approximately 25% of MDS patients. [13][14][15][16] Additional mutant genes, including ASXL1, CBL, ETV6, EZH2, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, and TP53, have been identified in smaller proportions of patients, particularly in those with high risk of leukemic evolution. 17 In a recent study, mutations in 5 of these genes have been found to be predictors of poor overall survival (OS), independently of established risk factors.…”

Section: Introductionmentioning

confidence: 99%

Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms

Malcovati

Papaemmanuil

Bowen

et al. 2011

Blood

450

350

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In a previous study, we identified somatic mutations of SF3B1, a gene encoding a core component of RNA splicing machinery, in patients with myelodysplastic syndrome (MDS). Here, we define the clinical significance of these mutations in MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). The coding exons of SF3B1 were screened using massively parallel pyrosequencing in patients with MDS, MDS/MPN, or acute myeloid leukemia (AML) evolving from MDS. Somatic mutations of SF3B1 were found in 150 of 533 (28.1%) patients with MDS, 16 of 83 (19.3%) with MDS/MPN, and 2 of 38 (5.3%) with AML. There was a significant association of SF3B1 mutations with the presence of ring sideroblasts (P < .001) and of mutant allele burden with their proportion (P = .002). The mutant gene had a positive predictive value for ring sideroblasts of 97.7% (95% confidence interval, 93.5%-99.5%). In multivariate analysis including established risk factors, SF3B1 mutations were found to be independently associated with better overall survival (hazard ratio = 0.15, P = .025) and lower risk of evolution into AML (hazard ratio = 0.33, P = .049). The close association between SF3B1 mutations and disease phenotype with ring sideroblasts across MDS and MDS/MPN is consistent with a causal relationship. Furthermore, SF3B1 mutations are independent predictors of favorable clinical outcome, and their incorporation into stratification systems might improve risk assessment in MDS.

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TET2 mutation is an independent favorable prognostic factor in myelodysplastic syndromes (MDSs)

Cited by 254 publications

References 31 publications

Comprehensive array CGH of normal karyotype myelodysplastic syndromes reveals hidden recurrent and individual genomic copy number alterations with prognostic relevance

Comprehensive array CGH of normal karyotype myelodysplastic syndromes reveals hidden recurrent and individual genomic copy number alterations with prognostic relevance

Molecular basis of myelodysplastic/myeloproliferative neoplasms

Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms

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