Alterations of the p16INK4a/p14ARF pathway in clear cell sarcoma.
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.
Department of Anatomic Pathology (Second Department of Pathology), Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
Tomonari
T
Takahira
Yoshinao
Y
Oda
Sadafumi
S
Tamiya
Hidetaka
H
Yamamoto
Kenichi
K
Kawaguchi
Chikashi
C
Kobayashi
Yukihide
Y
Iwamoto
Masazumi
M
Tsuneyoshi
D000328:Adult; D002648:Child; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis*; D004252:DNA Mutational Analysis; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D019942:Genes, p16; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D018227:Sarcoma, Clear Cell / Q000235:genetics*; D012983:Soft Tissue Neoplasms / Q000235:genetics*; D016019:Survival Analysis; D025803:Tumor Suppressor Protein p14ARF / Q000096:biosynthesis*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF