The Experts below are selected from a list of 23331 Experts worldwide ranked by ideXlab platform
Felicitas Thol - One of the best experts on this subject based on the ideXlab platform.
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IDH1/2 mutations in acute myeloid leukemia patients and risk of coronary artery disease and cardiac dysfunction—a retrospective propensity score analysis
Leukemia, 2020Co-Authors: Badder Kattih, Amir Shirvani, Piroska Klement, Abel Martin Garrido, Razif Gabdoulline, Alessandro Liebich, Maximilian Brandes, Anuhar Chaturvedi, Timon Seeger, Felicitas TholAbstract:Clonal hematopoiesis of indeterminate potential (CHIP) is linked to leukemia gene mutations and associates with an increased risk for coronary artery disease and poor prognosis in ischemic cardiomyopathy. Two recurrently mutated genes in CHIP and adult acute myeloid leukemia (AML) encode for isocitrate dehydrogenases 1 and 2 ( IDH1 and IDH2 ). Global expression of mutant IDH2 in transgenic mice-induced dilated cardiomyopathy and muscular dystrophy. In this retrospective observational study, we investigated whether mutant IDH1/2 predisposes to cardiovascular disease in AML patients. Among 363 AML patients, IDH1 and IDH2 mutations were detected in 26 (7.2%) and 39 patients (10.7%), respectively. Mutant IDH1 patients exhibited a significantly higher prevalence of coronary artery disease (26.1% vs. 6.4%, p = 0.002). Applying inverse probability-weighting analysis, patients with IDH1/2 mutations had a higher risk for a declining cardiac function during AML treatment compared to IDH1/2 wild type patients [left ventricular ejection fraction pretreatment compared to 10 months after diagnosis: 59.2% to 41.9% ( p
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IDH1 mutations in patients with myelodysplastic syndromes are associated with an unfavorable prognosis
Haematologica, 2010Co-Authors: Felicitas Thol, Eva M. Weissinger, Jürgen Krauter, Katharina Wagner, Frederik Damm, Martin Wichmann, Gudrun Göhring, Christiane Schumann, Gesine Bug, Oliver G. OttmannAbstract:Background Myelodysplastic syndromes are a heterogeneous group of hematopoietic stem cell disorders with a high propensity to transform into acute myeloid leukemia. Heterozygous missense mutations in IDH1 at position R132 and in IDH2 at positions R140 and R172 have recently been reported in acute myeloid leukemia. However, little is known about the incidence and prognostic impact of IDH1 and IDH2 mutations in myelodysplastic syndromes. Design and Methods We examined 193 patients with myelodysplastic syndromes and 53 patients with acute myeloid leukemia arising from myelodysplastic syndromes for mutations in IDH1 (R132), IDH2 (R172 and R140), and NPM1 by direct sequencing. Results We found that mutations in IDH1 occurred with a frequency of 3.6% in myelodysplastic syndromes (7 mutations in 193 patients) and 7.5% in acute myeloid leukemia following myelodysplastic syndromes (4 mutations in 53 patients). Three mutations in codon R140 of IDH2 and one mutation in codon R172 were found in patients with acute myeloid leukemia following myelodysplastic syndromes (7.5%). No IDH2 R140 or R172 mutations were identified in patients with myelodysplastic syndromes. The presence of IDH1 mutations was associated with a shorter overall survival (HR 3.20; 95% CI 1.47–6.99) and a higher rate of transformation into acute myeloid leukemia (67% versus 28%, P =0.04). In multivariate analysis when considering karyotype, transfusion dependence and International Prognostic Scoring System score, IDH1 mutations remained an independent prognostic marker in myelodysplastic syndromes (HR 3.57; 95% CI 1.59–8.02; P =0.002). Conclusions These results suggest that IDH1 mutations are recurrent molecular aberrations in patients with myelodysplastic syndromes, and may become useful as a poor risk marker in these patients. These findings await validation in prospective trials.
Deborah J. Chute - One of the best experts on this subject based on the ideXlab platform.
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The role of a monoclonal antibody 11C8B1 as a diagnostic marker of IDH2-mutated sinonasal undifferentiated carcinoma
Modern Pathology, 2019Co-Authors: Snjezana Dogan, Denise Frosina, Miriam Fayad, Thais Basili Oliveira, Barbara Alemar, Marc Rosenblum, Laura H. Tang, Meera Hameed, Ronald A. Ghossein, Deborah J. ChuteAbstract:IDH2 R172 mutations occur in >80% sinonasal undifferentiated carcinomas (“SNUC”) and ~80% of these are R172S and R172T variants. We examined the utility of the monoclonal antibody 11C8B1 to IDH2 R172S in IDH2 R172-mutated tumors to establish an immunohistochemistry protocol as a surrogate method for IDH2 R172S mutation detection. Eighty-eight formalin-fixed paraffin-embedded tumors including 42 sinonasal tumors and a variety of IDH1/2- mutated malignancies were tested by immunohistochemistry. The IDH1/2 mutation status was determined in 86 cases by a targeted massively parallel sequencing MSK-IMPACT^TM assay. Interestingly, monoclonal antibody 11C8B1 was reactive with all IDH2 R172S ( N = 15) mutated tumors including 12 sinonasal carcinomas, 2 high-grade sarcomas and one intrahepatic cholangiocarcinoma, and with all R172T ( N = 3) mutated sinonasal carcinomas displaying a distinct granular cytoplasmic labeling in all R172S/T mutated malignancies. 11C8B1 immunohistochemistry was also positive in 2 of 6 IDH1 R132S-mutated tumors, including one intrahepatic cholangiocarcinoma and one chondrosarcoma showing a smooth homogeneous cytoplasmic staining pattern. All IDH2 R172G/K/M/W ( N = 22) and IDH1 132H/C/G/L ( N = 15) mutated tumors, and all IDH1/2 -wild-type tumors ( N = 25), including a histologic variety of 23 sinonasal tumors, were immunonegative. Importantly, 11 sinonasal undifferentiated carcinomas ( N = 14, 79%) and 3 (100%) high-grade neuroendocrine carcinomas, large cell type were 11C8B1 immunopositive. Literature search revealed a virtual absence of IDH2 R172 and IDH1 R132S mutations in >1000 cases of 8 different malignancies included in the differential diagnosis of sinonasal undifferentiated carcinoma. Our study suggests that positive IDH2 11C8B1 immunohistochemistry in sinonasal carcinomas would be highly predictive of the presence of IDH2 R172S/T mutations and could serve as a reliable adjunct diagnostic marker of sinonasal undifferentiated carcinomas in >70% cases.
Ayalew Tefferi - One of the best experts on this subject based on the ideXlab platform.
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differential prognostic effect of IDH1 versus idh2 mutations in myelodysplastic syndromes a mayo clinic study of 277 patients
Leukemia, 2012Co-Authors: Mrinal M Patnaik, Curtis A Hanson, Janice M Hodnefield, Terra L Lasho, Christy Finke, Ryan A Knudson, Rhett P Ketterling, Animesh Pardanani, Ayalew TefferiAbstract:Unlike the case with acute myeloid leukemia, there is limited information on the prognostic impact of isocitrate dehydrogenase (IDH) mutations in myelodysplastic syndromes (MDS). In the current study of 277 patients with MDS, IDH mutations were detected in 34 (12%) cases: 26 IDH2 (all R140Q) and 8 IDH1 (6 R132S and 2 R132C). Mutational frequency was 4% (2 of 56) in refractory anemia with ring sideroblasts, 12% (16 of 130) in refractory cytopenia with multilineage dysplasia, 14% (2 of 14) in MDS-unclassifiable, 14% (6 of 42) in refractory anemia with excess blasts (RAEB)-1 and 23% (8 of 35) in RAEB-2. Normal karyotype was noted in all but one IDH1-mutated cases and 13 IDH2-mutated cases. Multivariable analysis identified presence of mutant IDH1 (P=0.0004; hazard ration 4.0, 95% confidence interval 1.9-8.8), revised International Prognostic Scoring System risk category (P<0.0001), and red cell transfusion need (P=0.002) as independent predictors of inferior survival. In a similar multivariable analysis, mutant IDH1 was the only variable associated with shortened leukemia-free survival (P=0.001; hazard ration 7.0, 95% confidence interval 2.3-20.8). The presence of IDH2R140Q did not affect the overall (P=0.54) or leukemia-free (P=0.81) survival. The current study suggests a powerful adverse prognostic effect for mutant IDH1 in MDS.
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differential prognostic effect of IDH1 versus idh2 mutations in myelodysplastic syndromes a mayo clinic study of 277 patients
Blood, 2011Co-Authors: Mrinal M Patnaik, Curtis A Hanson, Janice M Hodnefield, Terra L Lasho, Christy Finke, Ryan A Knudson, Rhett P Ketterling, Animesh Pardanani, Ayalew TefferiAbstract:Abstract 971 Unlike the case in acute myeloid leukemia, there is limited information on the prognostic impact of IDH mutations in myelodysplastic syndromes (MDS). In the current study of 277 patients with MDS, IDH mutations were detected in 34 (12%) cases: 26 IDH2 (all R140Q) and 8 IDH1 (six R132S and two R132C). Mutational frequency was 4% (2 of 56) in refractory anemia with ring sideroblasts (RARS), 12% (16 of 130) in refractory cytopenia with multilineage dysplasia, 14% (2 of 14) in MDS-unclassifiable, 14% (6 of 42) in refractory anemia with excess blasts (RAEB)-1, and 23% (8 of 35) in RAEB-2. Normal karyotype was noted in all but one IDH1-mutated cases and 13 IDH2-mutated cases. Multivariable analysis identified presence of mutant IDH1 (p=0.0004; HR 4.0, 95% CI 1.9–8.8), revised International Prognostic Scoring System (IPSS-R) risk category (p Disclosures: No relevant conflicts of interest to declare.
Twinkal C Pansuriya - One of the best experts on this subject based on the ideXlab platform.
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r132c IDH1 mutations are found in spindle cell hemangiomas and not in other vascular tumors or malformations
American Journal of Pathology, 2013Co-Authors: Kyle C Kurek, Twinkal C Pansuriya, Maayke A J H Van Ruler, Sofie L J Verbeke, Brendy E W M Van Den Akker, Valerie L Luks, Harry P W Kozakewich, Raf Sciot, Dina Lev, Alexander J LazarAbstract:Spindle cell hemangioma (SCH) is a rare, benign vascular tumor of the dermis and subcutis. The lesions can be multifocal and are overrepresented in Maffucci syndrome, in which patients also have multiple enchondromas. Somatic mosaic R132C IDH1 hotspot mutations were recently identified in Maffucci syndrome. We evaluated the presence of mutations in solitary and multiple SCHs in patients without multiple enchondromas and tested a range of other vascular lesions that enter into the differential diagnosis. The R132C IDH1 mutation was identified by hydrolysis probes assay and confirmed by Sanger sequencing in 18 of 28 (64%) SCHs; of the 10 negative cases, 2 harbored a mutation in IDH2 (R172T and R172M) by Sanger sequencing. None of 154 other vascular malformations and tumors harbored an IDH1 R132C mutation, and R132H IDH1 mutations were absent in all 182 cases. All 16 SCHs examined by immunohistochemistry were negative for expression of HIF-1α. In conclusion, 20 of 28 (71%) SCHs harbored mutations in exon 4 of IDH1 or IDH2 . Given that mutations were absent in 154 other vascular lesions, the mutation seems to be highly specific for SCH. The mutation does not induce expression of HIF-1α in SCH, and therefore the exact mechanism by which mutations in IDH1 or IDH2 lead to vascular tumorigenesis remains to be established.
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somatic mosaic IDH1 and idh2 mutations are associated with enchondroma and spindle cell hemangioma in ollier disease and maffucci syndrome
Nature Genetics, 2011Co-Authors: Twinkal C Pansuriya, Ronald Van Eijk, Pio Dadamo, Maayke A J H Van Ruler, Marieke L Kuijjer, Jan Oosting, Annemarie Cletonjansen, Jolieke G Van Oosterwijk, Sofie L J Verbeke, Danielle MeijerAbstract:Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier disease) combined with spindle cell hemangiomas (Maffucci syndrome). We report somatic heterozygous mutations in IDH1 (c.394C>T encoding an R132C substitution and c.395G>A encoding an R132H substitution) or IDH2 (c.516G>C encoding R172S) in 87% of enchondromas (benign cartilage tumors) and in 70% of spindle cell hemangiomas (benign vascular lesions). In total, 35 of 43 (81%) subjects with Ollier disease and 10 of 13 (77%) with Maffucci syndrome carried IDH1 (98%) or IDH2 (2%) mutations in their tumors. Fourteen of 16 subjects had identical mutations in separate lesions. Immunohistochemistry to detect mutant IDH1 R132H protein suggested intraneoplastic and somatic mosaicism. IDH1 mutations in cartilage tumors were associated with hypermethylation and downregulated expression of several genes. Mutations were also found in 40% of solitary central cartilaginous tumors and in four chondrosarcoma cell lines, which will enable functional studies to assess the role of IDH1 and IDH2 mutations in tumor formation.
Guo Gord Zhu - One of the best experts on this subject based on the ideXlab platform.
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genomic profiling identifies association of IDH1 idh2 mutation with longer relapse free and metastasis free survival in high grade chondrosarcoma
Clinical Cancer Research, 2020Co-Authors: Guo Gord Zhu, Khedoudja Nafa, Narasimhan P. Agaram, Ahmet Zehir, Ryma Benayed, Justyna Sadowska, Laetitia Borsu, Ciara Marie Kelly, William D. TapAbstract:Purpose: Chondrosarcomas are the second most common primary malignant bone tumors. Although histologic grade is the most important factor predicting the clinical outcome of chondrosarcoma, it is subject to interobserver variability. Isocitrate dehydrogenase 1 (IDH1) and IDH2 hotspot mutations were recently found to be frequently mutated in central chondrosarcomas. However, a few published articles have been controversial regarding the association between IDH1/IDH2 mutation status and clinical outcomes in chondrosarcomas. Experimental Design: We performed hotspot sequencing of IDH1 and IDH2 genes in 89 central chondrosarcomas and targeted next-generation sequencing in 54 of them, and then correlated the IDH1/IDH2 mutation status with the patient9s clinical outcome. Results: Although no association was discovered between IDH mutation status and the patient9s overall survival, IDH1/IDH2 mutation was found to be associated with longer relapse-free and metastasis-free survival in high-grade chondrosarcomas. Genomic profiling reveals TERT gene amplification and ATRX mutation, for the first time, in addition to TERT promoter mutation in a subset (6/30, 20%) of high-grade and dedifferentiated chondrosarcomas. These abnormalities in telomere genes are concurrent with IDH1/IDH2 mutation and with CDKN2A/2B deletion or TP53 mutation, suggesting a possible association and synergy among these genes in chondrosarcoma progression. We found 21% of patients with chondrosarcoma also had histories of second malignancies unrelated to cartilaginous tumors, suggesting possible unknown genetic susceptibility to chondrosarcoma. Conclusions: IDH1/IDH2 mutations are associated with longer relapse-free and metastasis-free survival in high-grade chondrosarcomas, and they tend to co-occur with TERT mutations and with CDKN2A/2B and TP53 alterations in a subset of high-grade chondrosarcomas.
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Genomic Profiling Identifies Association of IDH1/IDH2 Mutation with Longer Relapse-Free and Metastasis-Free Survival in High-Grade Chondrosarcoma
Clinical cancer research : an official journal of the American Association for Cancer Research, 2019Co-Authors: Guo Gord Zhu, Khedoudja Nafa, Narasimhan P. Agaram, Ahmet Zehir, Ryma Benayed, Justyna Sadowska, Laetitia Borsu, Ciara Marie Kelly, William D. Tap, Nicola FabbriAbstract:Purpose: Chondrosarcomas are the second most common primary malignant bone tumors. Although histologic grade is the most important factor predicting the clinical outcome of chondrosarcoma, it is subject to interobserver variability. Isocitrate dehydrogenase 1 (IDH1) and IDH2 hotspot mutations were recently found to be frequently mutated in central chondrosarcomas. However, a few published articles have been controversial regarding the association between IDH1/IDH2 mutation status and clinical outcomes in chondrosarcomas. Experimental Design: We performed hotspot sequencing of IDH1 and IDH2 genes in 89 central chondrosarcomas and targeted next-generation sequencing in 54 of them, and then correlated the IDH1/IDH2 mutation status with the patient9s clinical outcome. Results: Although no association was discovered between IDH mutation status and the patient9s overall survival, IDH1/IDH2 mutation was found to be associated with longer relapse-free and metastasis-free survival in high-grade chondrosarcomas. Genomic profiling reveals TERT gene amplification and ATRX mutation, for the first time, in addition to TERT promoter mutation in a subset (6/30, 20%) of high-grade and dedifferentiated chondrosarcomas. These abnormalities in telomere genes are concurrent with IDH1/IDH2 mutation and with CDKN2A/2B deletion or TP53 mutation, suggesting a possible association and synergy among these genes in chondrosarcoma progression. We found 21% of patients with chondrosarcoma also had histories of second malignancies unrelated to cartilaginous tumors, suggesting possible unknown genetic susceptibility to chondrosarcoma. Conclusions: IDH1/IDH2 mutations are associated with longer relapse-free and metastasis-free survival in high-grade chondrosarcomas, and they tend to co-occur with TERT mutations and with CDKN2A/2B and TP53 alterations in a subset of high-grade chondrosarcomas.
