Altered expression and molecular abnormalities of cell-cycle-regulatory proteins in rhabdomyosarcoma

• Published in: Modern pathology Vol. 17; no. 6; pp. 660 - 669
• Main Authors: Takahashi, Yukiko, Oda, Yoshinao, Kawaguchi, Ken-ichi, Tamiya, Sadafumi, Yamamoto, Hidetaka, Suita, Sachiyo, Tsuneyoshi, Masazumi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2004; Elsevier Limited
• Subjects: Adolescent; Base Sequence; Cell Cycle Proteins - analysis; Cell Cycle Proteins - genetics; cell-cycle-regulatory proteins; Child; children; Cyclin D1 - analysis; Cyclin E - analysis; Cyclin-Dependent Kinase Inhibitor p16 - analysis; Cyclin-Dependent Kinase Inhibitor p27; DNA Mutational Analysis; DNA, Neoplasm - chemistry; DNA, Neoplasm - genetics; DNA-Binding Proteins - analysis; E2F Transcription Factors; E2F1 Transcription Factor; Exons - genetics; Female; Gene Amplification; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Ki-67 Antigen - analysis; Male; Mutation; Nuclear Proteins - analysis; Nuclear Proteins - genetics; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Proto-Oncogene Proteins - analysis; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins c-mdm2; Proto-Oncogene Proteins p21(ras) - analysis; Proto-Oncogene Proteins p21(ras) - genetics; Retinoblastoma Protein - analysis; rhabdomyosarcoma; Rhabdomyosarcoma - genetics; Rhabdomyosarcoma - metabolism; Rhabdomyosarcoma - pathology; Rhabdomyosarcoma, Alveolar - genetics; Rhabdomyosarcoma, Alveolar - metabolism; Rhabdomyosarcoma, Alveolar - pathology; Rhabdomyosarcoma, Embryonal - genetics; Rhabdomyosarcoma, Embryonal - metabolism; Rhabdomyosarcoma, Embryonal - pathology; Transcription Factors - analysis; Tumor Suppressor Protein p53 - analysis; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Proteins - analysis; cell-cycle-regulatory proteins; rhabdomyosarcoma; children
• ISSN: 0893-3952; 1530-0285
• DOI: 10.1038/modpathol.3800101

Rhabdomyosarcoma is the most commonly occurring soft-tissue sarcoma in children. Some reports have discussed the altered expression and molecular abnormalities of cell-cycle-regulatory proteins in rhabdomyosarcoma; however, variable frequencies of occurrence have been noted. In the current study, among 72 cases of rhabdomyosarcoma, the authors evaluated for the expression of p53, MDM2, p16, p21/WAF1, p27, cyclin D1, cyclin E, pRb and E2F-1 protein immunohistochemically and assessed for proliferative activities using MIB-1. We also analyzed the mutation of the p53 gene in 45 cases, the amplification of the MDM2 gene in 18 cases and the mutation of the H-ras gene in 29 cases, using formalin-fixed paraffin-embedded materials. Furthermore, we assessed the correlation between clinicopathologic factors and the results of both immunohistochemical and molecular analyses. Alveolar type affected older patients, and it had a significantly higher mitotic rate compared with the embryonal type (P=0.0226). p53 overexpression was detected in 22 (30.6%) of 72 cases, and 10 (22.2%) of 45 cases had p53 gene abnormalities. As for MDM2, its overexpression was found in nine (12.5%) of 72 cases, and three (16.7%) of 18 cases showed MDM2 amplification. A statistically significant association was observed between immunoreaction for MDM2 and p53 overexpression (P=0.0002), and p53 and MDM2 overexpression was significantly correlated with high MIB-1 labeling indices. E2F-1 labeling indices showed a significantly higher score in alveolar type compared with that seen in embryonal type (P=0.0334), but MIB-1 did not. In conclusion, our study suggests that p53 overexpression may be related to tumor progression because tumors with p53 overexpression have a high proliferative activity in the current study. Alveolar type had a significantly higher both mitotic rate and E2F-1 labeling indices when compared with the embryonal type. The current study is the first report of the correlation of E2F-1 with alveolar rhabdomyosarcoma.