Alterations of the p16INK4a/p14ARF pathway in clear cell sarcoma

Tomonari Takahira, Yoshinao Oda, Sadafumi Tamiya, Hidetaka Yamamoto, Kenichi Kawaguchi, Chikashi Kobayashi, Yukihide Iwamoto, Masazumi Tsuneyoshi

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25 Citations (Scopus)


Clear cell sarcoma (CCS) is a very rare soft tissue sarcoma with a polor prognosis. It has become apparent through immunohistochemical, ultrastructural, and microarray analyses that CCS is a soft tissue melanocytic neoplasm. Alterations in the p16INK4a/p14ARF gene are common in malignant melanoma, which is the prototypical melanocytic neoplasm. In the present study, we performed a clinicopathologic analysis and investigated p16 and cyclin D1 expression by immunohistochemistry in 14 cases. Furthermore, we investigated genetic changes of various tumor suppressor genes and an oncogene, including p16INK4a/p14ARF, p53, β-catenin, and APC, in 11 cases. The 5-year overall survival rate in all the patients was 33.3%. A high mitotic rate was a significant adverse prognostic factor (P=0.004). Decreased expression of p16 was observed in 4 (28.6%) of 14 cases. Overexpression of cyclin D1 was observed in 9 cases (64.3%). SSCP analysis followed by DNA direct sequencing revealed point mutations of the p16INK4a gene in 2 of 11 cases (18.2%). In addition, one case with the p14ARF mutation and 2 cases with the p53 mutation were observed. None of the cases harbored mutation of the β-catenin or APC gene. Homozygous deletion of the p16INK4a/p14ARF gene was detected in one case. Methylation-specific PCR did not reveal hypermethylation of the p16INK4a/p14ARF promoter region in any of the cases. Three cases harbored genetic alterations of the p16INK4a/p14ARF gene (27.3%). All tumors with genetic alterations of the p16INK4a/p14ARF or p53 gene showed a high mitotic rate or tumor necrosis. These alterations were cordered to be influential in the poor prognosis of CCS patients.

Original languageEnglish
Pages (from-to)651-655
Number of pages5
JournalCancer Science
Issue number8
Publication statusPublished - Aug 2004

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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