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

Abstract

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 ¼ 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 ¼ 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 ¼ 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.

Immunoglobulin G is present in a wide variety of soft tissue tumors and correlates well with proliferation markers and tumor grades

“…[23][24][25][26][27][28][29][30] Musella et al demonstrated that cyclin D1 overexpression was an independent factor for survival in patients with sarcoma, 11 and their results were confirmed in other reports. 13,31,32 Although some investigators have demonstrated an inverse correlation between p53 immunopositivity and survival in patients with sarcoma, 9,[33][34][35] more have demonstrated that p53 has no association with patient prognosis. 13,23,26,[36][37][38][39] In the current study, clinical follow-up data on the patients with sarcoma was insufficient to establish a meaningful correlation between clinical outcome and Ig expression.…”

“…13,31,32 Although some investigators have demonstrated an inverse correlation between p53 immunopositivity and survival in patients with sarcoma, 9,[33][34][35] more have demonstrated that p53 has no association with patient prognosis. 13,23,26,[36][37][38][39] In the current study, clinical follow-up data on the patients with sarcoma was insufficient to establish a meaningful correlation between clinical outcome and Ig expression. However, because Igj expression correlated well with the LI of PCNA, Ki-67, and cyclin D1, it is reasonable to suggest that Ig expression also will correlate with patient clinical outcome.…”

“…For p53, sarcomas were considered positive when >10% of nuclei were immunolabeled for p53. [12][13][14] For PCNA, Ki-67, and cyclin D1, the percentages of positive tumor cells were estimated by counting approximately 3000 tumor cells and expressed as a labeling index (LI). 15 The LIs for all marker proteins were counted in almost identical fields of adjacent sections.…”

HRAS mutations in Costello syndrome: Detection of constitutional activating mutations in codon 12 and 13 and loss of wild‐type allele in malignancy

“…We have demonstrated the loss of wild-type HRAS with retention of the activated HRAS allele in a patient with recurrent biphasic ERMS/fibrosarcoma. Interestingly, HRAS mutations are rarely seen in sporadic rhabdomyosarcoma [Yoo and Robinson, 1999;Takahashi et al, 2004] implicating an alternate mechanism of rhabdomyosarcogenesis in patients with CS.…”

Immunostaining for peroxisome proliferator gamma distinguishes dedifferentiated liposarcoma from other retroperitoneal sarcomas

“…Given that dysregulation of cell-cycle machinery has variable tumor specificity, it follows that elevated levels of CDK4 and MDM2 proteins can be detected by immunohistochemistry in a number of sarcoma types. [9][10][11][25][26][27] Interestingly, however, recent reports suggest that these markers are also useful to distinguish some poorly differentiated sarcomas from dedifferentiated liposarcoma. 7,8 We recognize that the histologic evidence of a well-differentiated component is the so-called 'gold standard' for the diagnosis of dedifferentiated liposarcoma.…”