title: Cell cycle regulators in multiple myeloma: prognostic implications of p53 nuclear accumulation.
abstract: Multiple myeloma (MM) is characterized by a multistep process of tumorigenesis involving genes that control cell cycle progression. The prevalence and clinical implications of p53, p21, HDM-2, p27, and cyclin E immunoreactivity in MM patients, however, have not been fully elucidated. We evaluated the immunoreactivity (IR) for p53, p21, HDM-2, p27, cyclin E, and Ki-67 in bone marrow biopsies from 48 patients. In 34 (70.8%) cases, TP53 gene mutations and HDM-2 gene amplification were analyzed by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and Southern blot densitometric analyses in the corresponding bone marrow aspirates. Nineteen (39.6%) biopsy specimens exhibited > or =10% neoplastic cells immunoreactive for p53, 23 (47.9%) for p21, 28 (58.3%) for HDM-2, 29 (60.4%) for cyclin E, and 16 (33.3%) for Ki-67; 23 (47.9%) tumors had > or =50% neoplastic cells immunoreactive for p27. TP53 gene mutations in exons 5 through 8 were detected in 3 (8.8%) cases, whereas none exhibited HDM-2 gene amplification. In the cases bearing a wild-type TP53 gene, no association was found between p53 accumulation and HDM-2 or p21 IR. The same cases had been previously investigated for the presence of the t(11;14) translocation and cyclin D1 IR; interestingly, a significant inverse correlation between cyclin D1 and p27 or cyclin E IR was noted. In addition to clinical stage and Bartl's histologic stage and grade, p53 accumulation was significantly associated with survival, and it maintained its prognostic significance in a multivariate analysis adjusted for age, clinical stage, and relapse. Our data suggest that the immunohistochemical evaluation of p53 IR in bone marrow biopsies may represent an adjunct in MM patient prognostication.
authors.affiliation: Division of Pathology and Laboratory Medicine, European Institute of Oncology and University of Milan, School of Medicine, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Pruneri
authors.forename: Nadia
authors.initials: N
authors.lastname: Carboni
authors.forename: Luca
authors.initials: L
authors.lastname: Baldini
authors.forename: Daniela
authors.initials: D
authors.lastname: Intini
authors.forename: Mariangela
authors.initials: M
authors.lastname: Colombi
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertolini
authors.forename: Stefano
authors.initials: S
authors.lastname: Valentini
authors.forename: Patrick
authors.initials: P
authors.lastname: Maisonneuve
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viale
authors.forename: Antonino
authors.initials: A
authors.lastname: Neri
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D019927:Cyclin E / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D008875:Middle Aged; D009101:Multiple Myeloma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D009124:Muscle Proteins; D009687:Nuclear Proteins; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C493956:CDKN1A protein, human; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004273:DNA, Neoplasm; D019394:Ki-67 Antigen; D008840:Microfilament Proteins; D009124:Muscle Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C058992:Tagln protein, mouse; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2