Alterations of the p16INK4a/p14ARF pathway in clear cell sarcoma

Cancer Sci. 2004 Aug;95(8):651-5. doi: 10.1111/j.1349-7006.2004.tb03324.x.


Clear cell sarcoma (CCS) is a very rare soft tissue sarcoma with a poor 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, beta-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 beta-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 considered to be influential in the poor prognosis of CCS patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Child
  • Cyclin-Dependent Kinase Inhibitor p16 / biosynthesis*
  • DNA Mutational Analysis
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic*
  • Genes, p16
  • Humans
  • Immunohistochemistry
  • Male
  • Middle Aged
  • Prognosis
  • Sarcoma, Clear Cell / genetics*
  • Soft Tissue Neoplasms / genetics*
  • Survival Analysis
  • Tumor Suppressor Protein p14ARF / biosynthesis*


  • Cyclin-Dependent Kinase Inhibitor p16
  • Tumor Suppressor Protein p14ARF