IDH1 and IDH2 mutations are frequent in Chinese patients with acute myeloid leukemia but rare in other types of hematological disorders

Zou, Yang; Zeng, Yun; Df, Zhang; Zou, Shanhua; Cheng, Yunfeng; Yao, Yong‐Gang

doi:10.1016/j.bbrc.2010.10.038

Cited by 38 publications

(37 citation statements)

References 35 publications

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“…10,11 Finally, isocitrate dehydrogenase (IDH), which catalyzes the oxidative decarboxylation of isocitrate, is frequently mutated in specific types of cartilaginous tumors, hematological malignancies, and gliomas. [12][13][14] The currently known mechanisms underlying tumorigenesis linked to defects in the TCA cycle are well reviewed. 15,16 Defects in the SDH, FH, and IDH genes inhibit prolyl hydroxylases, leading to decreased hydroxylation of hypoxia-inducible factor-α.…”

Section: © American College Of Medical Genetics and Genomicsmentioning

confidence: 99%

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

Evenepoel

Papathomas

Krol

et al. 2015

Genetics in Medicine

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The tricarboxylic acid (TCA) cycle enzyme succinate dehydrogenase (SDH) is a heterotetramer protein complex consisting of four subunits encoded by nuclear genes. These include SDHA and SDHB, which form the catalytic domain, and SDHC and SDHD, which anchor the complex to the inner mitochondrial membrane. 1 The assembly factors, SDHAF1 and SDHAF2, ensure both structural and functional integrity of the complex. 2,3 SDH, also called mitochondrial complex II, is the only enzyme involved in both the electron transport chain and the TCA cycle, where it catalyzes the oxidation of succinate to fumarate. 1 The TCA cycle is central to the metabolism of sugars, lipids, and amino acids and is a major source of adenosine triphosphate in cells. In addition, the cycle also seems to be involved in tumorigenesis; enzymes of the TCA cycle are involved in the pathogenesis of several tumor types. SDH mutations have been involved in the etiopathogeny of pheochromocytomas (PCCs), paragangliomas (PGLs), gastrointestinal stromal tumors (GISTs), renal-cell carcinomas (RCCs), and pituitary adenomas (PAs). 1,2,[4][5][6][7][8][9] In addition, mutations in fumarate hydratase (FH), another member of the TCA cycle and which catalyzes the hydration of fumarate to malate, predispose to tumor formation, including RCCs, cutaneous and uterine leiomyomas, and PCCs/PGLs. 10,11 Finally, isocitrate dehydrogenase (IDH), which catalyzes the oxidative decarboxylation of isocitrate, is frequently mutated in specific types of cartilaginous tumors, hematological malignancies, and gliomas. 12-14 The currently known mechanisms underlying tumorigenesis linked to defects in the TCA cycle are well reviewed. 15,16 Defects in the SDH, FH, and IDH genes inhibit prolyl hydroxylases, leading to decreased hydroxylation of hypoxia-inducible factor-α. This results in activation of the hypoxia pathway, which supports tumor formation by activating angiogenesis, glucose metabolism, cell motility, and cell survival. Furthermore, defects in these enzymes lead to epigenetic alterations through an accumulation of oncometabolites inhibiting α-ketoglutarate-dependent dioxygenases, which are involved in DNA and histone demethylation. In addition to SDH-associated tumorigenesis, constitutional complex II deficiencies caused by SDHA, SDHB, SDHD, and SDHAF1 mutations may also lead to Leigh syndrome, infantile leukodystrophies, and cardiomyopathy. 3,[17][18][19] In the current review, our aim is to report all currently known SDH mutations and define their nature and spectrum in SDHrelated tumors, including PCCs/PGLs, GISTs, RCCs, and PAs, as well as in other unusual tumors arising in SDH mutation carriers. We performed bioinformatics analysis using SIFT, Polyphen2, and Mutation Assessor and compared the results with those of SDHA/SDHB immunohistochemistry (IHC) to predict the functional impact of nonsynonymous mutations. Finally, we explored and report here the nature of the second hit in all tumors arising in the SDH deficiency setting. The tricarboxylic acid, or Krebs, cycle is cent...

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Section: © American College Of Medical Genetics and Genomicsmentioning

confidence: 99%

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

Evenepoel

Papathomas

Krol

et al. 2015

Genetics in Medicine

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“…Subsequently, the mutation was also detected in myeloproliferative neoplasm (Pardanani et al, 2010;Tefferi et al, 2010), myelodysplastic syndrome (Kosmider et al, 2010), and non-Hodgkin lymphoma (Zou et al, 2010). Only three IDH-mutated cases were so far identified in ALL (Kang et al, 2009;Abbas et al, 2010;Andersson et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…The most popular method is direct sequencing (Abbas et al, 2010;Andersson et al, 2011). In addition, single-strand conformation polymorphism-based assays (Kang et al, 2009;Zou et al, 2010) and real-time PCR with post-PCR fluorescence melting curve analysis assays (Lin et al, 2011;Noordermeer et al, 2011) were also used. The immunohistochemistry with the anti-IDH1 R132H antibody (Kato et al, 2009;Byers et al, 2012) allows the observation of IDH1 R132H-positive cells in the clinical samples and leads to diffused staining by the antibody in almost every single cell of IDH1 R132H-positive tumor.…”

Section: Discussionmentioning

confidence: 99%

“…Subsequent to the detection of the IDH1 mutation, mutations at arginine 140 and 172 of IDH2 were also detected in AML (Boissel et al, 2010;Marcucci et al, 2010). IDH2 mutations occurred with a frequency of up to 11% in AML (Abbas et al, 2010;Paschka et al, 2010;Patel et al, 2011;Zou et al, 2010) and were mutually exclusive with mutations in IDH1 (Marcucci et al, 2010). Some studies showed that the IDH2 mutation had no impact on the prognosis (Thol et al, 2010), whereas some other studies provided evidence that the mutation had an unfavorable impact on the complete remission rate and overall survival (Boissel et al, 2010;Marcucci et al 2010).…”

Section: Introductionmentioning

confidence: 99%

“…In addition to AML, the IDH mutation was also found in a variety of hematologic malignancies, including myelodysplastic syndromes (Kosmider et al, 2010), myeloproliferative diseases (Pardanani et al, 2010;Tefferi et al, 2010), and nonHodgkin lymphoma (Zou et al, 2010). So far, only a few IDHmutated cases have been identified in ALL.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Mutation Analysis of Isocitrate Dehydrogenase in Acute Lymphoblastic Leukemia

Zhang

Wei

Tang

et al. 2012

Genetic Testing and Molecular Biomarkers

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Molecular Subtypes ofKIT/PDGFRAWild-Type Gastrointestinal Stromal Tumors

et al. 2016

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IMPORTANCE Wild-type (WT) gastrointestinal stromal tumors (GISTs), which lack KIT and PDGFRA gene mutations, are the primary form of GIST in children and occasionally occur in adults. They respond poorly to standard targeted therapy. Better molecular and clinical characterization could improve management. OBJECTIVE To evaluate the clinical and tumor genomic features of WT GIST. DESIGN, SETTING, AND PARTICIPANTS Patients enrolled in an observational study at the National Institutes of Health starting in 2008 and were evaluated in a GIST clinic held once or twice yearly. Patients provided access to existing medical records and tumor specimens. Self-referred or physician-referred patients younger than 19 years with GIST or 19 years or older with known WT GIST (no mutations in KIT or PDGFRA) were recruited; 116 patients with WT GIST were enrolled, and 95 had adequate tumor specimen available. Tumors were characterized by immunohistochemical analysis (IHC) for succinate dehydrogenase (SDH) subunit B, sequencing of SDH genes, and determination of SDHC promoter methylation. Testing of germline SDH genes was offered to consenting patients and families. MAIN OUTCOMES AND MEASURES For classification, tumors were characterized by SDHA, B, C, or D (SDHX) mutations and other genetic and epigenetic alterations, including presence of mutations in germline. Clinical characteristics were categorized. RESULTS Wild-type GIST specimens from 95 patients (median age, 23 [range, 7–78] years; 70% female) were classified into 3 molecular subtypes: SDH-competent (n = 11), defined by detection of SDHB by IHC; and 2 types of SDH-deficient GIST (n = 84). Of SDH-deficient tumors, 63 (67%) had SDH mutations, and in 31 of 38 (82%), the SDHX mutation was also present in germline. Twenty-one (22%) SDH-deficient tumors had methylation of the SDHC promoter leading to silencing of expression. Mutations in known cancer-associated pathways were identified in 9 of 11 SDH-competent tumors. Among patients with SDH-mutant tumors, 62% were female (39 of 63), median (range) age was 23 (7–58) years, and approximately 30% presented with metastases (liver [12 of 58], peritoneal [6 of 58], lymph node [15 of 23]). SDHC-epimutant tumors mostly affected young females (20 of 21; median [range] age, 15 [8–50] years), and approximately 40% presented with metastases (liver [7 of 19], peritoneal [1 of 19], lymph node [3 of 8]). SDH-deficient tumors occurred only in the stomach and had an indolent course. CONCLUSIONS AND RELEVANCE An observational study of WT GIST permitted the evaluation of a large number of patients with this rare disease. Three molecular subtypes with implications for prognosis and clinical management were identified.

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IDH1 and IDH2 mutations are frequent in Chinese patients with acute myeloid leukemia but rare in other types of hematological disorders

Cited by 38 publications

References 35 publications

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

Mutation Analysis of Isocitrate Dehydrogenase in Acute Lymphoblastic Leukemia

Molecular Subtypes ofKIT/PDGFRAWild-Type Gastrointestinal Stromal Tumors

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