Dataset Information

Prevalence and Prognostic Value of IDH1 R132 Mutation in Newly Diagnosed AML Egyptian Patients with Normal Karyotype.

ABSTRACT: Mutation in IDH1 gene was suggested to be associated with bad prognosis in cytogenetically normal AML (CN-AML). However, there are conflicting data about its prognostic impact. Besides, its prevalence and prognostic significance in Egyptian patients still not fully stated. We aimed to assess the prevalence of IDH1R132 mutation in Egyptian CN-AML patients, its correlation with FAB subtypes, and clinical outcome of those patients. Sequencing of amplified IDH1 gene exon four from 50 patients was performed to detect codon R132 point mutation. High prevalence of IDH1 mutation was detected in our patients (9/50, 18 %). Mutated IDH1R132 was associated with older age and higher platelets count (p = 0.04 and 0.01 respectively). The most common FAB subtype associated with mutated IDH1R132 was AML-M2 followed by M4. In multivariate analysis, IDH1R132 mutation was found as independent prognostic variable. It was significantly associated with lower CR and shorter OS (p = 0.06 and 0.009 respectively).

SUBMITTER: Salem D

PROVIDER: S-EPMC5280846 | biostudies-other | 2017 Mar

REPOSITORIES: biostudies-other

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Publications

Prevalence and Prognostic Value of IDH1 R132 Mutation in Newly Diagnosed AML Egyptian Patients with Normal Karyotype.

Salem Dalia D El-Aziz Sherin Abd SA El-Menshawy Nadia N Abouzeid Tarek T Ebrahim Mohamed M

Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion 20160218 1

Mutation in IDH1 gene was suggested to be associated with bad prognosis in cytogenetically normal AML (CN-AML). However, there are conflicting data about its prognostic impact. Besides, its prevalence and prognostic significance in Egyptian patients still not fully stated. We aimed to assess the prevalence of IDH1<sup>R132</sup> mutation in Egyptian CN-AML patients, its correlation with FAB subtypes, and clinical outcome of those patients. Sequencing of amplified IDH1 gene exon four from 50 pati ...[more]

PMID: 28194056

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Project description:Shwachman-Diamond syndrome (SDS) is a rare and systemic disease mostly caused by mutations in the SBDS gene and characterized by pancreatic insufficiency, skeletal abnormalities, and a bone marrow dysfunction. In addition, SDS patients are predisposed to develop myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), typically during adulthood and associated with TP53 mutations. Although most SDS diagnoses are established in childhood, the nature and frequency of serial bone marrow cell investigations during the patients' lifetime remain a debatable topic. The precise molecular mechanisms leading to AML progression in SDS patients have not been fully elucidated because the patient cohorts are small and most disease monitoring is conducted using standard histological and cytogenetic approaches. Here we report a rare case of a patient with SDS who was diagnosed with AML at 5 years of age and survived. Intermittent neutropenia preceded the AML diagnostic but serial bone marrow monitoring according to the standard of care revealed no cytogenetic anomalies nor signs of clonal hematopoiesis. Using next generation sequencing approaches to find cytogenetically cryptic pathogenic mutations, we identified the cancer hotspot mutation c.394C>T/p.Arg132Cys in IDH1 with high variant allelic frequency in bone marrow cells, suggesting clonal expansion of a major leukemic clone karyotypically normal, in the SDS-associated AML. The mutation was somatic and likely occurred at the leukemic transformation stage, as it was not detected in a matched normal tissue nor in bone marrow smear prior to AML diagnosis. Gain-of-function mutations in IDH1, such as c.394C>T/p.Arg132Cys, create a neo-activity of isocitrate dehydrogenase 1 converting ?-ketoglutarate into the oncometabolite D-2-hydroxyglutarate, inhibiting ?-ketoglutarate-dependent enzymes, such as histone and DNA demethylases. Overall, our results suggest that along with previously described abnormalities such as TP53 mutations or monosomy7, 7q-, which are all absent in this patient, additional mechanisms including IDH1 mutations drive SDS-related AML and are likely associated with variable outcomes. Sensitive techniques complementary to standard cytogenetics, such as unbiased or targeted panel-based next generation sequencing approaches, warrant testing for monitoring of myelodysplasia, clonal hematopoiesis, and leukemia in the context SDS. Such analyses would also assist treatment decisions and allow to gain insight into the disease biology.

Dataset Information

Prevalence and Prognostic Value of IDH1 R132 Mutation in Newly Diagnosed AML Egyptian Patients with Normal Karyotype.

Publications

Prevalence and Prognostic Value of IDH1 R132 Mutation in Newly Diagnosed AML Egyptian Patients with Normal Karyotype.

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