RAS mutation in acute myeloid leukemia is associated with distinct cytogenetic subgroups but does not influence outcome in patients younger than 60 years.
The pathogenesis of acute myeloid leukemia (AML) involves the cooperation of mutations promoting proliferation/survival and those impairing differentiation. The RAS pathway has been implicated as a key component of the proliferative drive in AML. We have screened AML patients, predominantly younger than 60 years and treated within 2 clinical trials, for NRAS (n = 1106), KRAS (n = 739), and HRAS (n = 200) hot-spot mutations using denaturing high-performance liquid chromatography or restriction fragment length polymorphism (RFLP) analysis. NRAS mutations were confirmed in 11% of patients (126/1106) and KRAS mutations in 5% (39/739). No HRAS mutations were detected in 200 randomly selected samples. Codons most frequently mutated were N12 (43%), N13 (21%), and K12 (21%). KRAS mutations were relatively overrepresented in French-American-British (FAB) type M4 (P < .001). NRAS mutation was over-represented in the t(3;5)(q21 approximately 25;q31 approximately q35) subgroup (P < .001) and underrepresented in t(15;17)(q22;q21) (P < .001). KRAS mutation was overrepresented in inv(16)(p13q22) (P = .004). Twenty-three percent of KRAS mutations were within the inv(16) subgroup. RAS mutation and FLT3 ITD were rarely coexistent (14/768; P < .001). Median percentage of RAS mutant allele assayed by quantitative RFLP analysis was 28% (N12), 19% (N13), 25% (N61), and 21% (K12). RAS mutation did not influence clinical outcome (overall/disease-free survival, complete remission, relapse rate) either for the entire cohort or within cytogenetic risk groups.
Bowen
David T
DT
Division of Pathology & Neuroscience, Ninewells Hospital, Dundee DD1 9SY, United Kingdom. d.t.bowen@dundee.ac.uk
Frew
Marion E
ME
Hills
Robert
R
Gale
Rosemary E
RE
Wheatley
Keith
K
Groves
Michael J
MJ
Langabeer
Stephen E
SE
Kottaridis
Panagiotis D
PD
Moorman
Anthony V
AV
Burnett
Alan K
AK
Linch
David C
DC
D000208:Acute Disease; D000367:Age Factors; D020732:Cytogenetic Analysis; D004252:DNA Mutational Analysis; D011905:Genes, ras; D006801:Humans; D007951:Leukemia, Myeloid / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D017720:Molecular Epidemiology; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D016019:Survival Analysis; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3; D018631:ras Proteins / Q000235:genetics*
D011518:Proto-Oncogene Proteins; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D018631:ras Proteins