FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia

The prevalence and significance of genetic abnormalities in older patients with acute myeloid leukemia (AML) are unknown. Polymerase chain reactions and single-stranded conformational polymorphism analyses were used to examine 140 elderly AML patients enrolled in the Southwest Oncology Group study 9...

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Bibliographic Details
Published in:Blood 2001-06, Vol.97 (11), p.3589-3595
Main Authors: Stirewalt, Derek L., Kopecky, Kenneth J., Meshinchi, Soheil, Appelbaum, Frederick R., Slovak, Marilyn L., Willman, Cheryl L., Radich, Jerald P.
Format: Article
Language:English
Subjects:
Aged
Aged, 80 and over
Aging
Biological and medical sciences
Exons
fms-Like Tyrosine Kinase 3
Gene Frequency
Genes, ras - genetics
Hematologic and hematopoietic diseases
Humans
Leukemia, Myeloid, Acute - genetics
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Medical sciences
Middle Aged
Mutation
Polymerase Chain Reaction
Polymorphism, Single-Stranded Conformational
Prognosis
Proto-Oncogene Proteins - genetics
Receptor Protein-Tyrosine Kinases - genetics
Tumor Suppressor Protein p53 - genetics
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Summary:The prevalence and significance of genetic abnormalities in older patients with acute myeloid leukemia (AML) are unknown. Polymerase chain reactions and single-stranded conformational polymorphism analyses were used to examine 140 elderly AML patients enrolled in the Southwest Oncology Group study 9031 for FLT3, RAS, and TP53 mutations, which were found in 34%, 19%, and 9% of patients, respectively. All but one of the FLT3 (46 of 47) mutations were internal tandem duplications (ITDs) within exons 11 and 12. In the remaining case, a novel internal tandem triplication was found in exon 11. FLT3 ITDs were associated with higher white blood cell counts, higher peripheral blast percentages, normal cytogenetics, and less disease resistance. All RAS mutations (28 of 28) were missense point mutations in codons 12, 13, or 61. RASmutations were associated with lower peripheral blast and bone marrow blast percentages. Only 2 of 47 patients with FLT3 ITDs also had a RAS mutation, indicating a significant negative association between FLT3 and RAS mutations (P = .0013). Most TP53 mutations (11 of 12) were missense point mutations in exons 5 to 8 and were associated with abnormal cytogenetics, especially abnormalities in both chromosomes 5 and 7. FLT3 and RAS mutations were not associated with inferior clinical outcomes, but TP53mutations were associated with a worse overall survival (median 1 versus 8 months, P = .0007). These results indicate that mutations in FLT3, RAS, or TP53 are common in older patients with AML and are associated with specific AML phenotypes as defined by laboratory values, cytogenetics, and clinical outcomes.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood.V97.11.3589