Familial hematological malignancies: new IDH2 mutation

Abstract

Isocitrate dehydrogenase IDH 1 and IDH 2 mutations were reported in several cancer forms, especially in hematological malignancies, but were never been investigated in familial aggregation. The aim of this study is to determine whether germline isocitrate dehydrogenase genes mutations are involved.We targeted IDH1 and IDH2 genes in 104 familial cases belonging to Tunisian and French populations, including several forms of hematological malignancies and cosegregated solid tumors.We report one IDH1 variant: c.315 G>T, p.Gly105Gly in 15 % of cases, which was assigned to the worst outcome in several studies. Three IDH2 variants were found, among them, one intronic substitution c.543+45 G>A (rs142033117) and two new variants not previously described: c.389 A>T, p.Lys130Met and c.414 T>C, p.Thr138Thr. The p.Lys130Met was found in one case diagnosed with Waldenstrom's disease with familial history of cancer. The enrolled in silico analysis, the functional study, and the absence of this variant in control population strengthen the hypothesis of its deleterious effect.From an extended number of candidate genes analyzed in familial hematological malignancies, IDH2 might be considerably involved since we reported a potential damaging effect.

Germline mutations among Polish patients with acute myeloid leukemia

“…Mutations and polymorphisms in these genes, predominantly somatic, are reported in 5-15 % of AML patients [27][28][29]. In AML, nearly all IDH2 mutations cause a single amino acid substitution, Arg172 to one of four different residues -Lys, Met, Gly, and Trp, and Arg140 to either Gln or Trp [29,30]. Following the discoveries in glioma and AML, mutations in IDH2 gene were found in multiple types of human tumors, including thyroid carcinomas, cartilaginous tumors, and intrahepatic cholangiocarcinoma [31].…”

IDH2 (isocitrate dehydrogenase 2 (NADP+), mitochondrial)

“…Germline IDH mutations were searched for in 104 familial cases of hematological malignancies/cosegregated solid tumors. IDH1 and IDH2 variants were found respectively in 15 % and 3% of cases (Hamadou et al, 2016).…”

Rescue of TCA Cycle Dysfunction for Cancer Therapy

“…Three variants that occur in exon 4 were discovered upon IDH2 gene screening: c.543+45G>A, c. 389 A>T, p. Lys120Met and c.414 T>C, and p.Thr138Thr. These gene variants were found in two independent patients classified under French and Tunisian familial cases which, despite ethnic differences, were similarly diagnosed with non-Hodgkin lymphoma [48]. Melissa Carbonneau et al found that the molecular mechanism underlying the oncogenic activity of mutant IDH1/2 involved mTOR signaling via KDM4A inhibition, an αKG-dependent enzyme [35].…”