Prognostic importance of mutations in the ras proto-oncogenes in de novo acute myeloid leukemia

Abstract

Mutations of the N- and K-ras genes are the most frequent genetic aberrations in acute myeloid leukemia (AML) and their detection in preleukemic conditions such as the myelodysplastic syndrome (MDS) suggests a role in the earliest phases of leukemogenesis. Despite these observations, little is known about the clinical importance of ras mutations in AML. We studied the clinical impact of ras mutations in 99 patients with de novo AML. All patients were treated in two prospective multicenter trials. The polymerase chain reaction was used to amplify areas surrounding the codons 12, 13, and 61 of the three ras genes N-, K-, and H-ras from DNA from bone marrow cells, ras mutations were detected by an algorithm based on allele-specific oligonucleotide hybridization. Eighteen of 99 (18%) patients harbored mutations in either N- or K-ras. All of the observed mutations occurred in N-ras (N = 10) and K-ras (N = 5) or concurrently in both N- and K-ras (N = 3). There were no significant differences between ras-negative and ras- positive patients according to age, sex, blood counts, cytogenetic abnormalities, or French-American-British classification. However, univariate analysis suggested a longer survival in ras-positive patients (P = .11). When adjusted for age, which was the most important factor affecting outcome, the presence of a ras mutation emerged as a significant predictor for improved survival (P = .03) and along with lower bone marrow blast counts (P = .02) and better cytogenetic category (P = .01). However, the presence of an aberrant ras allele was strongly correlated with lower bone marrow blast counts (P = .007). Thus, whether a mutation in the N-ras or K-ras proto-oncogenes directly affects treatment outcome or indirectly through an association with lower leukemic burden remains to be determined. Nevertheless, these findings counter the prevailing bias that oncogene mutations lead to more aggressive behavior in human malignancies.

Addressing Nonlinearity in the Exposure‐Response Relationship for a Genotoxic Carcinogen: Cancer Potency Estimates for Ethylene Oxide

“…However, even though EO is capable of producing such effects, gene mutations have not been considered to be the initiating events for the chemically mediated leukemias in humans. While specific oncogene mutations (e.g., in N-ras and K-ras (Neubauer et al, 1994)) have been reported in a proportion of de novo leukemias, the chromosome aberrations described above are the characteristic changes found in the chemically induced leukemias (USEPA, 1997b;Levine & Bloomfield, 1992;Yunis et al, 1989).…”

Clinical and proteomic characterization of acute myeloid leukemia with mutated RAS

“…[1][2][3] They are present overall in approximately 40% of all malignancies, and noted in up to 90% of pancreatic adenocarcinoma, 30% of non-small cell lung cancer, and approximately one-third of colorectal cancers. 1,2 Several series have reported RAS mutations in 10% to 25% of cases of acute myeloid leukemia (AML) [4][5][6][7][8][9][10][11][12][13][14] and 7% to 48% of cases of myelodysplastic syndrome. [15][16][17] N-RAS, K-RAS, and H-RAS are the most common isoforms of RAS involved in human cancer.…”

Genetic Abnormalities as Targets for Molecular Therapies in Myelodysplastic Syndromes

“…[11][12][13][14][15][16] RAS proteins are a crucial component of the signaling transduction pathways and result in the control of cellular proliferation, differentiation, and cell death. [11][12][13][14][15][16] Under normal conditions, RAS activation is triggered by the binding of growth factors to plasma membrane receptors with tyrosine kinase activity. 14 The activation of these pathways is dependent on farnesylation.…”

“…In MDS, N-RAS mutations have been detected in 10-40% of cases. 16 These mutations have been associated with poor prognosis, higher incidence of transformation to AML, and shorter survival. Patients with abnormal karyotypes and N-RAS mutations have the highest likelihood of transformation.…”