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Blood, 15 September 2005, Vol. 106, No. 6, pp. 2113-2119.
Prepublished online as a Blood First Edition Paper on June 16, 2005; DOI 10.1182/blood-2005-03-0867.
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NEOPLASIA
RAS mutation in acute myeloid leukemia is associated with distinct cytogenetic subgroups but does not influence outcome in patients younger than 60 years
David T. Bowen,
Marion E. Frew,
Robert Hills,
Rosemary E. Gale,
Keith Wheatley,
Michael J. Groves,
Stephen E. Langabeer,
Panagiotis D. Kottaridis,
Anthony V. Moorman,
Alan K. Burnett, and
David C. Linch
From the Division of Pathology and Neuroscience, Ninewells Hospital, University of Dundee, Dundee, United Kingdom; the University of Birmingham Clinical Trials Unit, Birmingham, United Kingdom; the Department of Haematology, University College London, London, United Kingdom; Leukemia Research Fund (LRF) Cytogenetics Group, Cancer Sciences Division, University of Southampton, Southampton, United Kingdom; and the National Cancer Research Institute Adult Leukemia Working Party and Cardiff University, Cardiff, United Kingdom.
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 25;q31q35) 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. (Blood. 2005;106:2113-2119)
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