Mutations with loss of heterozygosity of p53 are common in therapy-relatedmyelodysplasia 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

Purpose: To study mutations and loss of heterozygosity (LOH) of p53 in ther apy-related myelodysplasia (t-MDS) and acute myeloid leukemia (I-AML). Patients and Methods: Fifty-two unselected patients with t-MDS and 25 patie nts with t-AML were studied by polymerase chain reaction (PCR)-single-stran d conformational polymorphism (SSCP) at the DNA level and by reverse transc riptase (RT)-PCR-SSCP at the mRNA level, and cases with aberrant SSCP patte rns were sequenced. Results: Somatically acquired mutations of p53 were observed in 21 of 77 ca ses 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 an d 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 cytoge netic 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 wi th duplication of the homologous chromosome 17 carrying the mutated p53 all ele. Mutations of p53 were significantly associated with deletion or loss o f 5q (P <.0001) and a complex karyotype (P =.0001), but surprisingly were n ot 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 e xtremely poor prognosis (P =.014), apparently restricted to the 15 cases wi th LOH of p53 (P =.046). Conclusion: Mutations with loss of function of p53 are significantly associ ated with deletion or loss of 5q in t-MDS and t-AML after previous treatmen t with alkylating agents and are associated with genetic instability, J Cli n Oncol 19:1405-1413, (C) 2001 by American Society of Clinical Oncology.