title: 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.
abstract: We examined chromosomes and molecular aberrations in 21 patients with therapy-related leukemias (t-AML) or myelodysplastic syndromes (t-MDS). All patients showed abnormal karyotypes, and chromosomal losses of No. 5 and/or No. 7 (-5/5q- 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 microsatellite instability, suggesting replication error (RER+) phenotype. Meanwhile, 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 samples from healthy volunteers or patients with other hematological disorders. Consequently, this study revealed a possible relationship of RER+ phenotype accompanying an hMSH2 alteration to the development of therapy-related AML/MDS in association with TP53 mutations and specific chromosomal losses, and suggests that some patients may be predisposed to myelodysplasia after chemotherapy for their primary tumor.
authors.affiliation: Third Department of Internal Medicine, Kyoto Prefectural University of Medicine, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Horiike
authors.forename: S
authors.initials: S
authors.lastname: Misawa
authors.forename: H
authors.initials: H
authors.lastname: Kaneko
authors.forename: Y
authors.initials: Y
authors.lastname: Sasai
authors.forename: M
authors.initials: M
authors.lastname: Kobayashi
authors.forename: H
authors.initials: H
authors.lastname: Fujii
authors.forename: S
authors.initials: S
authors.lastname: Tanaka
authors.forename: M
authors.initials: M
authors.lastname: Yagita
authors.forename: T
authors.initials: T
authors.lastname: Abe
authors.forename: K
authors.initials: K
authors.lastname: Kashima
authors.forename: M
authors.initials: M
authors.lastname: Taniwaki
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020137:Base Pair Mismatch; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5; D002897:Chromosomes, Human, Pair 7; D004261:DNA Replication; D004273:DNA, Neoplasm / Q000235:genetics; D004276:DNA, Satellite / Q000235:genetics; D005260:Female; D006801:Humans; D007938:Leukemia / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D007953:Leukemia, Radiation-Induced / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D016609:Neoplasms, Second Primary / Q000235:genetics / Q000473:pathology; D011877:Radionuclide Imaging; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D004273:DNA, Neoplasm; D004276:DNA, Satellite; D016159:Tumor Suppressor Protein p53