Multiple Point Mutation of N-<i>ras</i> and K-<i>ras</i> Oncogenes in Myelodysplastic Syndrome and Acute Myelogenous Leukemia

Abstract

We analyzed activating mutations of N-ras and K-ras by the polymerase chain reaction and oligonucleotide hybridization in hematological disorders. Activating mutations of these codons were detected in 4 of 20 cases of myelodysplastic syndrome (MDS) and 15 of 77 cases of acute myelogenous leukemia (AML). Out of 19 cases of MDS and AML who carried active mutations, 7 cases were found to have two or more distinct mutations in activating codons of N-ras and K-ras. Ras mutation was found preferentially in progressive disease such as refractory anemia with excess of blasts (RAEB) of RAEB in transformation (RAEB-t). A relatively high incidence of ras mutation was found in M₅ AML (40%). No ras mutations were found in other hematological disorders, such as acute lymphoblastic leukemia and chronic myelogenous-leukemia. The most frequent amino acid substitution was that of an aspartate for glycine at codon 12 of N-ras resulting from G to A mutation (11/35). The survival of AML patients who carried ras mutations showed no significant differences from those without ras mutations calculated by Kaplan-Meier. Seven cases of MDS and 7 cases of AML patients could be investigated at various points during their clinical course. Among these 14 cases, we found 2 interesting cases of MDS. The first case lost multiple clones carrying ras mutations during disease progression, the second case acquired mutation of the ras gene during disease progression. These results suggested that multiple point mutations of ras genes may not be initiating events but may contribute to a clonal evolution of MDS and AML.

Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia

“…Some studies have reported that KIT or RAS mutations confer a poor prognosis. 28,35,37,44,45 In this cohort of patients we were unable to demonstrate any significant a prognostic impact of RAS or KIT mutations, although this may be due to the fact that treatment was heterogeneous. The lack of a prognostic impact of KIT or RAS mutations is in marked contrast to the strong negative impact of FLT3/ITD mutations in our study population.…”

“…18,19,36,37 RAS mutations in pediatric AML have been previously reported, albeit, in smaller cohorts of patients (10-99 patients), with frequencies of 6-37%. 35,[38][39][40][41][42] In most studies NRAS mutations were more frequent than KRAS mutations, in agreement with our own study in which 14.7% of patients had a NRAS mutation and only 3.3% a KRAS mutation.…”

A comparative study of molecular mutations in 381 patients with myelodysplastic syndrome and in 4130 patients with acute myeloid leukemia

“…[31][32][33][34][35][36] In this study, as in most previous analyses, NRAS-mutations were among the most frequent mutations in MDS (≥6.5% of all cases), 38,41,42,57 and more frequent than FLT3-LM (≤3%). 23,24 Although the reported incidences of NRAS mutations in MDS range widely (probably due to different proportions of MDS subtypes in the various analyses), this study and all mentioned previous analyses found higher frequencies of NRAS mutations in the advanced stages of MDS than in the initial stages.…”

“…23,24 Although the reported incidences of NRAS mutations in MDS range widely (probably due to different proportions of MDS subtypes in the various analyses), this study and all mentioned previous analyses found higher frequencies of NRAS mutations in the advanced stages of MDS than in the initial stages. 41,42,57,58 This demonstrates an association between NRAS mutations and MDS transformation. NRAS mutations were further shown to be associated with karyotype evolution, e.g.…”

“…In MDS frequencies of NRAS mutations were reported to be between 7% and 48% in previous studies including series of up to 220 patients. [37][38][39][40][41][42] MLL-PTD occur in 10% of AML with normal karyotype and are associated with a poor prognosis.…”