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Prognostic importance of mutations in the ras proto-oncogenes in de novo
acute myeloid leukemia
A Neubauer, RK Dodge, SL George, FR Davey, RT Silver, CA Schiffer, RJ Mayer, ED Ball, D Wurster-Hill and CD Bloomfield
Department of Medicine, Lineberger Cancer Research Center, University of
North Carolina at Chapel Hill 27599-7295.
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.
Volume 83,
Issue 6,
pp. 1603-1611,
03/15/1994
Copyright © 1994 by The American Society of Hematology
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