The genetic predisposition to familial hematological malignancies has been previously reported highlighting inherited gene mutations. Several genes have been reported but genetic basis remains not well defined. In this study, we extended our investigation to a potential candidate GATA2 gene which was analyzed by direct sequencing in 119 cases including familial aggregations with a variety of hematological malignancies and sporadic acute leukemia belonging to Tunisian and French populations. We reported a deleterious p.Arg396Gln GATA2 mutation in one patient diagnosed with both sporadic acute myeloid leukemia (AML) and breast cancer. We also reported several GATA2 variations in familial cases. The absence of deleterious mutations in this large cohort of familial aggregations of hematological malignancies may strengthen the hypothesis that GATA2 mutations are an important predisposing factor, although as a secondary genetic event, required for the development of overt malignant disease.
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.
IGH gene rearrangement and IGK-Kde gene deletion
can be used as molecular markers for the assessment of B lineage acute lymphoblastic
leukemia (B-ALL). Minimal residual disease detected based on those markers is
currently the most reliable prognosis factor in B-ALL. The aim of this study was to
use clonal IGH/IGK-Kde gene rearrangements to confirm B-ALL
diagnosis and to evaluate the treatment outcome of Tunisian leukemic patients by
monitoring the minimal residual disease (MRD) after induction chemotherapy. Seventeen
consecutive newly diagnosed B-ALL patients were investigated by multiplex PCR assay
and real time quantitative PCR according to BIOMED 2 conditions. The vast majority of
clonal VH-JH rearrangements included VH3 gene. For IGK deletion, clonal VK1f/6-Kde
recombinations were mainly identified. These rearrangements were quantified to
follow-up seven B-ALL after induction using patient-specific ASO. Four patients had
an undetectable level of MRD with a sensitivity of up to 10-5. This
molecular approach allowed identification of prognosis risk group and adequate
therapeutic decision. The IGK-Kde and IGH gene
rearrangements might be used for diagnosis and MRD monitoring of B-ALL, introduced
for the first time in Tunisian laboratories.
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