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-, Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, et al. The middle vertical axis represents the pooled HR and the 2 vertical axes indicate the corresponding 95% CI. Privacy, Help 2013;11:838–874. N- and K-RAS exons 2 and 3 DNA mutation screening were performed by high-resolution melting PCR with the use of LightCycler 480 in High Melting Resolution Master Mix 1X (Roche Applied Science) with 10 ng of genomic DNA, primers 0.1 μmol/L each, and 25 mmol/L MgCl2. Statistical analyses were performed with the use of the SAS package version 9.01 (SAS Institute). https://bmccancer.biomedcentral.com/articles/10.1186/s12885-019-5602-8 Prevalence of TET2 mutations is indicated within brackets. provided patient samples; D.B. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Clinical and biologic characteristics of the population of 96 MDS patients. Hematology. We paid special attention on the 106,287,392-106,420,407 region of chromosome 4, which contains the TET2 gene (http://genome.ucsc.edu). However, the response rates to HMAs were significantly different between those with and without TET2 mutations, and the low expression level of TET2 gene was significantly associated with a poor OS in MDS patients. IQR indicates Interquartile Range (25%-75%). Itzykson R, Kosmider O, Cluzeau T, Mansat-De Mas V, Dreyfus F, Beyne-Rauzy O. et al. Little is known regarding the pathogenesis of MDS, although approximately 50% of MDS patients display karyotype aberrations in cytogenetic analyses.8  Recurrent molecular anomalies have been identified in less than 10% of MDS mainly advanced stages (for a review, see Nimer1 ). Semin Oncol. 5-hmC levels in patients with MDS with TET2 mutations were significantly lower than in those without mutations, and CD34+ cells of patients with MDS exhibited a lower 5-hmC content than that of controls. 2017 Jul;58:102-107. doi: 10.1016/j.leukres.2017.03.013. Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms. Testing for TET2 mutations will provide information for patient risk stratification, prognosis, and overall therapy guidance. The survival advantage resulted at least in part from less AML progression in the mutated patients. Myelodysplastic syndromes: clinical practice guidelines in oncology. Each point represents a separate study and horizontal line represents the mean effect size. Conflict-of-interest disclosure: The authors declare no competing financial interests. Blood. Mutations are also detected in 38% of peripheral T-cell lymphoma and 47% of angioimmunoblastic T-cell lymphoma. The group has further postulated that TET2 mutations are observed during the early steps of the disease [20] , and might influence the phenotype and clinical behavior of the disease. SNP array data were analyzed for signal intensity and SNP calls by use of the Gene Chip Genotyping Console 3.0.2 (GTC; Affymetrix). TET2 locus status corresponds to the number of anomalies detected by PCR and sequencing and to the anomalies of the 4q24 region. A list of Groupe Francophone des Myelodysplasies participants can be found in the supplemental Appendix, available on the Blood website. Other mutations in TP53, AML1/RUNX1, and N- or K-RAS genes have been reported with low prevalence in MDS.23,24,28-30  Some of the molecular abnormalities described in MDS have demonstrated unfavorable prognostic value, including NRAS and TP53 mutations or hypermethylation of p15INK4B.29-32  Those mutations were generally observed only in advanced stages or therapy-related diseases, and their prognostic value was generally not independent of other parameters, especially of IPSS. Clinical and hematological data were recorded after patients gave their informed consent in accordance with the Declaration of Helsinki. All 23 chips passed Affymetrix QC standards (Contrast QC: minimum 2.4, average 3.1; QC call rate minimum 96%, average 98%, median of the absolute values of all pairwise difference: maximum 0.33, average 0.26). However, the difference in OS at 3 years between mutated (n = 7) and unmutated (n = 27) patients within the Int-2/High risk group (n = 34) did not reach the significance (p = 0.092) probably as a result of the small size of this subgroup (supplemental Figure 3). Myelodysplastic syndromes. TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis. The combined hazard ratios (HR) estimated for overall survival (OS) was 1.00 (95%CI: 0.74 to 1.37; p=0.989) when comparing those with TET2 mutations with those without. Epub 2013 Mar 27. Therefore, we performed a meta-analysis. Curr Hematol Malig Rep. 2019 Dec;14(6):550-560. doi: 10.1007/s11899-019-00554-4. OS was measured as the time in months from diagnosis to death or censored at last patient's follow-up if no death occurred. This difference was significant (P = .035). Epub 2014 Mar 31. Roles of TET2 in Hematopoiesis and Hematopoietic Malignancies The prevalence of TET2 mutation was estimated with the 95% confidence interval (95% CI). Detection of mutant TET2 in myeloid malignancies other than myeloproliferative neoplasms: CMML, MDS, MDS/MPN and AML. Front Oncol. TET2 and/or DNMT3A mutations were associated with better ORR and favorable progression-free survival (PFS) upon treatment with DNMT inhibitors in MDS patients; ASXL1 and SF3B1 were associated with better OS . In this study, we examined the molecular profile of 15 MDS-relevant genes in 1 … We found mutations of the TET2 coding sequence in 22 of 96 MDS patients. Overall survival also was analyzed according to the IPSS in the group of 88 patients. 2020 Jan 1;11(2):508-519. doi: 10.7150/jca.30363. Contribution: O.K., V.G.-B., and M.C. Prognostic significance of Tet methylcytosine dioxygenase 2 (TET2) gene mutations in adult patients with acute myeloid leukemia: a meta-analysis. To estimate the overall response rate (ORR) of the combination of standard dose azacitidine and ascorbic acid in patients with MDS, AML, and MDS/MPN overlap with heterozygous Areas of copy number change (CN) and loss-of-heterozygosity (LOH) were investigated by use of the bioinformatic tools GTC version 3.0.2 (Affymetrix), DChip (http://biosun1.harvard.edu/complab/dchip/), and the Partek Genomics Suite (www.partek.com/). ),+mar,+var(17) /46,XY (4), ATCD chemotherapy or radiotherapy, yes/no (%), Erythropoiesis-stimulating agent with or without G-CSF. MDS patients of this cohort had a rather good prognosis (63.5% Low/Int1 and 36.5% Int-2/High risk), and only few of them received MDS-related therapy. This situation contrasts with inactivation of both copies of other tumor suppressor genes, either bi-allelic mutation of TP53, hypermethylation of p15INK4B locus or hypermethylation of CTNNA1 or FZD9 gene together with deletion that is associated with disease progression or therapy-related MDS.23-27. Please enable it to take advantage of the complete set of features! Accessibility TET2 anomalies were numbered according to European Molecular Biology Laboratory nucleotide sequence reference FM992369. The number of recurrently detected alterations is indicated by the text within each disc, as well as by disc size. ), and the Ligue Nationale Contre le Cancer (to O.A.B., W.V.). 2020 Oct;34(10):2592-2606. doi: 10.1038/s41375-020-0990-y. Among these, 2 studies evaluated the impact that the TET2 expression level had on the prognosis. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Overall 2 anomalies of TET2 were observed in the other half of the patients, which appeared preferentially to fall in the Low/Int-1 MDS. In the 2 other cases (UPN 210 and 211), the deletion of 4q24 was associated to a missense or a nonsense mutation on the remaining copy (Table 1). High-resolution single nucleotide polymorphism (SNP) array–based karyotyping recently has contributed to the detection of small genomic imbalance and acquired segmental uniparental disomy in MDS.9,10. Forest plots of the hazard ratios (HRs) and 95% confidence intervals for overall…, Figure 4. 2018 Dec;23(10):778-784. doi: 10.1080/10245332.2018.1471794. contributed equally to this work. Anomalies detected by the combination of sequencing and conventional cytogenetics. Mutation negative cases, not satisfying standard diagnostic criteria 5. Liu WJ, Tan XH, Luo XP, Guo BP, Wei ZJ, Ke Q, He S, Cen H. Leuk Lymphoma. https://ehoonline.biomedcentral.com/articles/10.1186/s40164-015-0009-y Mutation in one of five genes is independently associated with a decreased overall survival. Epub 2016 Mar 4. According to the WHO criteria, patients were classified as RA (n = 16), 5q-syndrome (n = 2), undefined MDS (MDS-U, n = 4), refractory cytopenia with multilineage dysplasia (RCMD, n = 7), RARS/RARS with thrombocytosis (RARS-T, n = 8), refractory cytopenia with multilineage dysplasia (RCMD) with ringed sideroblasts (n = 4), RA with an excess of blasts less than 10% (RAEB1, n = 25), RAEB more than 10% blasts (RAEB2, n = 23), and secondary AML with a bone-marrow blast count between 20% and 29% (n = 7). Correspondence: Michaëla Fontenay, Service d'Hématologie Biologique, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, F75679 Paris Cedex 14, France; e-mail: [email protected]. Proposals for the classification of the myelodysplastic syndromes. have observed that TET2 mutations appear as a frequent molecular event in MDS and are an independent predictor of good prognosis leading to a longer OS than unmutated patients. and V.G.-B. The time to AML transformation was defined as the time between diagnosis and documented transformation (≥ 30% bone-marrow blasts). All statistical analyses were 2-sided, and P values less than .05 were considered to have statistical significance. The differences in the prevalence were not statistically significant within subgroups of WHO, FAB, or IPSS classifications (Table 2). In univariate analysis, age, IPSS, number of cytopenia, percentage of bone-marrow blasts, IPSS-based unfavorable karytoype, and transfusion requirement were identified as OS prognostic factors. Mutations of TET2 In Myeloid Malignancies. 2016 Sep;21(8):454-61. doi: 10.1080/10245332.2015.1106815. Comparison between categorical variables was performed by χ2 or Fisher exact tests. Kaplan-Meier analysis also showed that the freedom from AML progression within 3 years was 89.3% (95% CI, 63.1%-97.0%] in the mutated group versus 63.7% [95% CI, 48.2%-75.4%) in the unmutated group (Figure 1B). Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. 2011;38:613–620. The prevalence of TET2 mutation was 21 (23.8%) in 88 patients. When present in MDS, IDH1 mutation is associated with shorter leukemia-free survival and decreased overall survival, whereas these impacts are not found in TET2 -mutated MDS [ 38, 39 ]. According to the FAB classification, patients were classified as RA (n = 29), RARS (n = 12), RAEB (n = 47), and RAEBt (n = 8). None of the patients devoid of TET2 mutation were mutated in the N- or K-RAS genes. found that TET2 mutations have no prognosis impact on OS of patients with MDS (HR 1.13, 95% CI: 0.81–1.5). Forest plots of the hazard ratios (HRs) and 95% confidence intervals for overall…, The middle vertical axis represents the pooled HR and the 2…, Figure 7. The acquired nature of the K1299G or L1872P substitutions could not be checked in 2 other patients, but substitution at K1299 and L1872 has already been reported as acquired.17-19  Likewise, L1872 and I1873 targeting has been described and lies within the catalytic domain of the TET2 homologue TET1.13  It is therefore unlikely that these alterations would be of germinal origin in these specific patients. Multivariate analysis including age, IPSS, and transfusion requirement demonstrates that TET2 mutation was an independent factor of favorable prognosis. In 12 cases, the mutational status was stable before and after disease progression, suggesting that mutations of TET2 gene are not linked to the onset of leukemia. Clonal TET2 mutations predicted response (odds ratio [OR] 1.99, P =.036) when subclones unlikely to be detected by Sanger sequencing (allele fraction <10%) were treated as wild-type (WT). TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Our results suggest that the determination of TET2 mutational status might assist risk stratification. Conclusions: 1) TET2 deletions are rare in TET2 mutated MDS (3%). Interestingly, 2 different anomalies of the TET2 coding sequence were detected in 5 patients, suggesting the alteration of the 2 copies of the TET2 gene (Table 1). 30-33 Similarly, patients with idiopathic … Du MY, Xu M, Deng J, Liu L, Guo T, Xia LH, Hu Y, Mei H. J Cancer. For TET2 gene analysis, polymerase chain reaction (PCR) and direct sequencing were performed starting from 20 ng of genomic DNA, as previously described.12  All reported TET2 mutations were scored on both strands by use of ABI 3300 capillary sequencers. A Kaplan-Meier curve showed that OS was significantly increased in patients with TET2 mutations (Figure 1A). TET2 mutations alone were significantly associated with thrombotic events (p= 0.031; OR= 3.56; 95% CI, 1.15-11.83) with 65% of patients with a thrombotic event harbouring a TET2 mutation When TET2 mutations were removed from the logistical regression analysis, there was no significant association between ASXL1 and DNMT3A mutations and thrombosis in patients with PV A, Lollipop plot showing type and location along the protein sequence of all the 343 TET2 MT identified in the combined MDS/MPN cohort. 9 Moreover, somatic mutations in MDS-associated genes have been identified in healthy individuals with CHIP. Data concerning treatments received during the period of follow-up were recorded for all patients. Comparison between categorical variables was performed by Chi-squared or Fisher exact tests. In these lymphomas, TET2 mutations are associated with aggressive disease and poor outcome. See this image and copyright information in PMC. Acquired mutations in TET2 are common in myelodysplastic syndromes. TET2 mutation; meta-analysis; myelodysplastic syndrome; prognosis. Chromosome 5q deletion and epigenetic suppression of the gene encoding alpha-catenin (CTNNA1) in myeloid cell transformation. Missense mutations were considered only when located in conserved regions spanning from 1134 to 1444 and 1842 to 1921 amino acids of the TET2 protein. and M.F. Ann Hematol. (A) Overall survival in mutated () and unmutated (—) MDS patients (n = 88, log-rank test, P = .005), (B) freedom from AML progression in mutated () and unmutated (—) MDS patients (n = 88, log-rank test; P = .035), and (C) event of death or AML transformation-free survival in mutated () and unmutated (—) MDS patients (n = 88, log-rank test, P = .032). Myelodysplastic syndromes: molecular pathogenesis and genomic changes. Methylation of the p15(INK4b) gene in myelodysplastic syndromes is frequent and acquired during disease progression. Mutations in the p53 gene in myelodysplastic syndromes. Prognostic significance of TET2 mutations in myelodysplastic syndromes: A meta-analysis. Refinement of the international prognostic scoring system (IPSS) by including LDH as an additional prognostic variable to improve risk assessment in patients with primary myelodysplastic syndromes (MDS). 2019 Apr 2;9:210. doi: 10.3389/fonc.2019.00210. AML indicates acute myeloid leukemia; F, female; FAB, French-British-American; IPSS, International Prognostic Scoring System; M, male; MDS-U, undefined myelodysplastic syndromes; RA, refractory anemia; RAEB, refractory anemia with excess blasts; RAEB1, RA with an excess of blasts less than 10%; RAEB2, RAEB more than 10% blasts; RAEBt, RAEB in transformation; RARS, refractory anemia with ringed sideroblasts; RARS-T, RARS with thrombocytosis; RCMD, refractory cytopenia with multilineage dysplasia; RCMD-RS, refractory cytopenia with multilineage dysplasia with ringed sideroblasts; TET, ten-eleven translocation; and WHO, World Health Organization. Despite being highly associated with therapy-related MDS, PPM1D The size of the blocks or diamonds represents the weight, the length of the straight line represents the width of 95% CI. Epub 2017 Mar 25. Anomalies detected by the combination of sequencing and SNP arrays. The majority of patients had a rather good prognosis according to IPSS, including 63.5% of Low/Int-1 and 36.5% Int-2/High risk. Role of nucleophosmin in embryonic development and tumorigenesis. In addition, TET2 mutations were also associated with longer survival, lower risk of transformation to AML, and a molecular marker for good prognosis in patients with MDS. Studies were distributed symmetrically and suggested there were no significant biases exist. The 2 PCR products were combined, cleaned-up, and end-labeled to be hybridized to the SNP array containing 1.8 million features with half of them specifically designed to detect copy number variations. New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. ASXL1 encodes a chromatin-binding protein involved in epigenetic eCollection 2020. According to the WHO criteria, patients were classified as RA (n = 16), 5q-syndrome (n = 2), undefined MDS (MDS-U, n = 4), refractory cytopenia with multilineage dysplasia (RCMD, n = 7), RARS/RARS with thrombocytosis (RARS-T, n = 8), RCMD with ringed sideroblasts (n = 4), RA with an excess of blasts less than 10% (RAEB1, n = 25), RAEB more than 10% blasts (RAEB2, n = 23), and secondary AML with a bone-marrow blast count between 20% and 29% (n = 7). The prevalence of TET2 mutation was 21 (23.8%) in 88 patients. When analyzing separately IPSS Low/Int-1 (n = 61) and Int-2/High (n = 35) risk groups, clinical and hematologic parameters were not different (supplemental Table 1). In MPN, mutations in JAK2 or MPL might cooperate with TET2 mutations to induce the clinical phenotype.12,15  The oncogenic events specifically cooperating with TET2 abnormalities during MDS pathogenesis remain to be identified that will allow the evaluation of their respective contribution to phenotype and clinical behavior in these neoplasms. Frameshift, nonsense, missense mutations, or defects in gene structure were identified in 22 (22.9%) of 96 patients (95% confidence interval [CI], 14.5-31.3 patients). According to the FAB classification, patients were classified as refractory anemia (RA; n = 29), refractory anemia with ringed sideroblasts (RARS; n = 12), refractory anemia with excess blasts (RAEB; n = 47), and RAEB in transformation (RAEBt; n = 8). Germline TET2 mutation was a poor prognosis factor in MDS patients via univariate analysis (HR=5.3, 95%CI: 0.89-32.2, P =0.0209), but not in multivariate analysis by Cox regression model ( P =0.062). FOIA Univariate and multivariate Cox regression analyses of the risk of death of mutated (n = 21) and unmutated (n = 67) groups of patients. We previously described 4 MDS and AML patients with acquired interstitial deletions affecting the 4q24 chromosomal region.11  Molecular and cytogenetic approaches allowed the identification of the ten-eleven translocation 2 (TET2) gene in a common 500-kb minimal deleted region.12  The TET2 gene comprises 11 exons spread over 150 kb.12  The 2002 amino acids predicted TET2 protein exhibits 2 evolutionary conserved regions: one region located from amino acid 1134 until amino acid 1444 and a second region located near the carboxyterminal end from amino acid 1842 until amino acid 1921 that is related to the hydroxylase family depend on iron and 2 oxoglutarate.13  We and others12,14-19  recently have reported the recurrent alteration of the TET2 gene in the stem cells of various myeloid disorders, including 20% of MDS and MDS/myeloproliferative neoplasm (MPN)–related AML and 8% to 15% of MPN. Multivariate Cox proportional hazards model was used to study the independent factors of death adjusted for TET2 mutation status, age (by 10-year increments), IPSS, and treatment by red blood-cell transfusions, these variables being statistically significant in univariate analyses. In the group of Low and Int-1 MDS (n = 54), mutated patients (n = 14) had significant longer survival within 5 years than unmutated patients (n = 40; P = .020). In sharp contrast, TET2 mutation is a favorable prognostic factor in MDS that is independent of IPSS. Begg's funnel plot for publication…, Figure 7. Kosmider et al. Begg's funnel plot for publication bias analysis, National Library of Medicine Conclusions: Some family members were asymptomatic carriers, which indicated germline TET2 mutation might have a family aggregation. There was no significant difference in age, sex, previous exposure to chemotherapy or radiotherapy, peripheral blood parameters, circulating blast cells, multilineage dysplasia, and IPSS-based karyotype distribution between mutated and unmutated cases. Forest plots of the hazard ratios (HRs) and 95% confidence intervals for overall…, Figure 3. ATCD indicates antecedent; G-CSF, granulocyte colony-stimulating factor; IPSS, International Prognostic Scoring System; MDS, myelodysplastic syndromes; MCV, mean corpuscular volume; and sAML, secondary acute myeloid leukemia. Low risk MDS pts having EZH2 and ASXL1 at higher risk than predicted by IPSS TP53 mutations strongly associated with shorter OS after adjustment for IPSS The publication costs of this article were defrayed in part by page charge payment. Unadjusted and adjusted hazards ratio and their 95% CI are provided. Flow diagram of selection process…, Figure 1. Mutations detected in 7 patients at diagnosis were always present, and no other change in the TET2 coding sequence was observed after progression.

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