Distinct genetic involvement of the TP53 gene in therapy-related leukemia and myelodysplasia with chromosomal losses of Nos 5 and/or 7 and its possible relationship to replication error phenotype

We examined chromosomes and molecular aberrations in 21 patients with thera py-related leukemias (t-AML) or myelodysplastic syndromes (t-MDS). All pati ents showed abnormal karyotypes, and chromosomal losses of No. 5 and/or No. 7 (-5/5 and/or -7/7q-) were identified in 12 patients. Among these 12, six patients (50%) harbored a TP53 mutation, and two of five examined showed m icrosatellite instability, suggesting replication error (RER+) phenotype. M eanwhile, among the other nine patients without -5/5q- and/or -7/7q-, none harbored a TP53 mutation, and none of five examined showed RER+ phenotype. Thus, TP53 mutations and RER+ phenotype were preferentially associated with specific chromosomal losses in t-AML/MDS. We then screened for mutational events in representative DNA mismatch repair genes; exons 5-7 and 12-15 of the hMSH2 gene and exon 9 of hMLH1. Notably, two unrelated patients showing RER+ phenotype had an identical missense alteration at codon 419 of hMSH2 in their marrow cells and fibroblasts, which were not found in 120 DNA samp les from healthy volunteers or patients with other hematological disorders. Consequently, this study revealed a possible relationship of RER+ phenotyp e accompanying an hMSH2 alteration to the development of therapy-related AM L/MDS in association with TP53 mutations and specific chromosomal losses, a nd suggests that some patients may be predisposed to myelodysplasia after c hemotherapy for their primary tumor.