title: RAS mutation in acute myeloid leukemia is associated with distinct cytogenetic subgroups but does not influence outcome in patients younger than 60 years.
abstract: 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.
authors.affiliation: Division of Pathology & Neuroscience, Ninewells Hospital, Dundee DD1 9SY, United Kingdom. d.t.bowen@dundee.ac.uk
authors.forename: David T
authors.initials: DT
authors.lastname: Bowen
authors.forename: Marion E
authors.initials: ME
authors.lastname: Frew
authors.forename: Robert
authors.initials: R
authors.lastname: Hills
authors.forename: Rosemary E
authors.initials: RE
authors.lastname: Gale
authors.forename: Keith
authors.initials: K
authors.lastname: Wheatley
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Groves
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Langabeer
authors.forename: Panagiotis D
authors.initials: PD
authors.lastname: Kottaridis
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Moorman
authors.forename: Alan K
authors.initials: AK
authors.lastname: Burnett
authors.forename: David C
authors.initials: DC
authors.lastname: Linch
mesh_terms: 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*
chemical_list: D011518:Proto-Oncogene Proteins; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D018631:ras Proteins