title: Genetic lesions associated with blastic transformation of polycythemia vera and essential thrombocythemia.
abstract: Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative disorders that may progress to acute leukemia in a subset of patients. This study aimed at investigating the genetic lesions associated with the blastic transformation of PV and ET. A panel of PV and ET cases at different stages of disease was analyzed for the presence of genetic alterations of TP53, NRAS, KRAS, and MDM2 by a combination of mutational analysis and Southern blot hybridization. The occurrence of microsatellite instability (MSI) was also tasted in selected cases. Samples of PV and ET analyzed in chronic phase disease were consistently devoid of all genetic lesions tested, suggesting that alterations of TP53, NRAS, KRAS, and MDM2 do not contribute significantly to development of chronic phase PV and ET. Conversely, mutations of TP53 were detected in 7/15 (46.6%) blastic phase cases, including 3/5 PV and 4/10 ET. In blastic phase patients for whom the corresponding chronic phase DNA was also available, it could be documented that the genetic lesion had arisen at the time of blastic transformation. In addition to TP53 mutations, cases of blastic phase PV and ET occasionally harbored mutations of NRAS (one case of blastic phase ET) or displayed MSI (one case of blastic phase PV). These data indicate that inactivation of TP53 is a relatively frequent event associated with the blastic transformation of PV and ET and may be responsible for the tumor progression of these disorders.
authors.affiliation: Dipartimento di Scienze Biomediche e Oncologia Umana, Università di Torino, Ospedale San Luigi, Orbassano, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Gaidano
authors.forename: C
authors.initials: C
authors.lastname: Pastore
authors.forename: V
authors.initials: V
authors.lastname: Santini
authors.forename: J
authors.initials: J
authors.lastname: Nomdedeu
authors.forename: B
authors.initials: B
authors.lastname: Gamberi
authors.forename: D
authors.initials: D
authors.lastname: Capello
authors.forename: F
authors.initials: F
authors.lastname: Vischia
authors.forename: L
authors.initials: L
authors.lastname: Resegotti
authors.forename: U
authors.initials: U
authors.lastname: Mazza
authors.forename: P R
authors.initials: PR
authors.lastname: Ferrini
authors.forename: F
authors.initials: F
authors.lastname: Lo Coco
authors.forename: G
authors.initials: G
authors.lastname: Saglio
mesh_terms: D000328:Adult; D000368:Aged; D001752:Blast Crisis / Q000235:genetics*; D015139:Blotting, Southern; D004247:DNA / Q000302:isolation & purification; D004252:DNA Mutational Analysis; D017931:DNA Primers; D015342:DNA Probes; D004273:DNA, Neoplasm / Q000302:isolation & purification; D018450:Disease Progression; D005260:Female; D016158:Genes, p53 / Q000235:genetics; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins; D011087:Polycythemia Vera / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2; D017422:Sequence Analysis, DNA; D013920:Thrombocythemia, Essential / Q000235:genetics* / Q000276:immunology / Q000473:pathology
chemical_list: D017931:DNA Primers; D015342:DNA Probes; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D004247:DNA; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2