title: Adverse impact of IDH1 and IDH2 mutations in primary AML: experience of the Spanish CETLAM group.
abstract: The study of genetic lesions in AML cells is helpful to define the prognosis of patients with this disease. This study analyzed the frequency and clinical impact of recently described gene alterations, isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) mutations, in a series of homogeneously treated patients with primary (de novo) AML. Two-hundred and seventy-five patients enrolled in the CETLAM 2003 protocol were analyzed. IDH1 and IDH2 mutations were investigated by well-established melting curve-analysis and direct sequencing (R140 IDH2 mutations). To establish the percentage of the mutated allele a pyrosequencing method was used. Patients were also studied for NPM, FLT3, MLL, CEBPA, TET2 and WT1 mutations. IDH1 or IDH2 mutations were identified in 23.3% AML cases and in 22.5% of those with a normal karyotype. In this latter group, mutations were associated with short overall survival. This adverse effect was even more evident in patients with the NPM or CEBPA mutated/FLT3 wt genotype. In all the cases analyzed, the normal allele was detected, suggesting that both mutations act as dominant oncogenes. No adverse clinical impact was observed in cases with TET2 mutations. IDH1 and IDH2 mutations are common genetic alterations in normal karyotype AML. Favourable genotype NPM or CEBPA mutated/FLT3 wt can be further categorized according to the IDH1 and IDH2 mutational status.
authors.affiliation: Hematology Department, Hosptial de Santa Creu i Sant Pau, Barcelona, Spain. jnomdedeu@santpau.es
authors.forename: J
authors.initials: J
authors.lastname: Nomdedéu
authors.forename: M
authors.initials: M
authors.lastname: Hoyos
authors.forename: M
authors.initials: M
authors.lastname: Carricondo
authors.forename: J
authors.initials: J
authors.lastname: Esteve
authors.forename: E
authors.initials: E
authors.lastname: Bussaglia
authors.forename: C
authors.initials: C
authors.lastname: Estivill
authors.forename: J M
authors.initials: JM
authors.lastname: Ribera
authors.forename: R
authors.initials: R
authors.lastname: Duarte
authors.forename: O
authors.initials: O
authors.lastname: Salamero
authors.forename: D
authors.initials: D
authors.lastname: Gallardo
authors.forename: C
authors.initials: C
authors.lastname: Pedro
authors.forename: A
authors.initials: A
authors.lastname: Aventin
authors.forename: S
authors.initials: S
authors.lastname: Brunet
authors.forename: J
authors.initials: J
authors.lastname: Sierra
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000502:physiology; D059785:Karyotype; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D011379:Prognosis; D012189:Retrospective Studies; D013030:Spain / Q000453:epidemiology; D016019:Survival Analysis; D055815:Young Adult
chemical_list: C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human