Mutations With Loss of Heterozygosity of p53 Are Common in Therapy-Related Myelodysplasia and Acute Myeloid Leukemia After Exposure to Alkylating Agents and Significantly Associated With Deletion or Loss of 5q, a Complex Karyotype, and a Poor Prognosis

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Abstract
PURPOSE: To study mutations and loss of heterozygosity (LOH) of p53 in therapy-related myelodysplasia (t-MDS) and acute myeloid leukemia (t-AML). PATIENTS AND METHODS: Fifty-two unselected patients with t-MDS and 25 patients with t-AML were studied by polymerase chain reaction (PCR)–single-strand conformational polymorphism (SSCP) at the DNA level and by reverse transcriptase (RT)-PCR–SSCP at the mRNA level, and cases with aberrant SSCP patterns were sequenced. RESULTS: Somatically acquired mutations of p53 were observed in 21 of 77 cases of t-MDS or t-AML, and 19 of these 21 patients had received alkylating agents. Single-base substitutions at A:T pairs were more common in t-MDS and t-AML, whereas single-base substitutions at G:C pairs are most common in MDS and AML de novo and in solid tumors. Six patients demonstrated a cytogenetic loss of 17p13, and these six and an additional nine patients with p53 mutations demonstrated LOH of p53 at the DNA or mRNA level. This suggests a cytogenetic loss of the normal p53 allele in these nine cases combined with duplication of the homologous chromosome 17 carrying the mutated p53 allele. Mutations of p53 were significantly associated with deletion or loss of 5q (P < .0001) and a complex karyotype (P = .0001), but surprisingly were not associated with deletion or loss of 7q (P = .73), and were infrequent in patients with balanced chromosome translocations (P = .03). Mutations of p53 were more common in older patients (P = .036) and were associated with an extremely poor prognosis (P = .014), apparently restricted to the 15 cases with LOH of p53 ( P = .046). CONCLUSION: Mutations with loss of function of p53 are significantly associated with deletion or loss of 5q in t-MDS and t-AML after previous treatment with alkylating agents and are associated with genetic instability.