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Mechanisms of inactivation of the p16 INK4a gene in leiomyosarcoma of soft tissue: decreased p16 expression correlates with promoter methylation and poor prognosis
Author(s) -
Kawaguchi Kenichi,
Oda Yoshinao,
Saito Tsuyoshi,
Yamamoto Hidetaka,
Tamiya Sadafumi,
Takahira Tomonari,
Miyajima Kimitaka,
Iwamoto Yukihide,
Tsuneyoshi Masazumi
Publication year - 2003
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.1419
Subject(s) - dna methylation , biology , methylation , promoter , immunohistochemistry , cancer research , microbiology and biotechnology , gene expression , gene , tumor suppressor gene , leiomyosarcoma , cell cycle , carcinogenesis , pathology , genetics , medicine , immunology
The p16 INK4a tumour suppressor gene, encoding p16 protein, plays a crucial role in regulation of the G1 cell‐cycle phase. To investigate the potential role of p16 in soft tissue leiomyosarcoma (LMS), an immunohistochemical analysis was performed of 77 LMSs for p16 expression. Decreased expression of the p16 protein was identified in 25 of 77 LMSs (32%). Decreased expression of p16 correlated significantly with large tumour size ( p = 0.0038). In a univariate analysis, large tumour size and decreased expression of p16 were statistically significant adverse prognostic factors ( p = 0.025 and p = 0.0021, respectively). In a multivariate analysis including conventional clinicopathological parameters, decreased expression of p16 protein was revealed as the only independent unfavourable prognostic factor ( p = 0.012). To elucidate the mechanisms of inactivation of the p16 INK4a gene, 49 LMSs for which genomic DNA was available were examined; analysis for homozygous deletion, mutation, and promoter hypermethylation was conducted using differential PCR, PCR–SSCP, and methylation‐specific PCR, respectively. Promoter hypermethylation was detected in 11 of 49 LMS cases (22%); homozygous deletion was detected in 3 of 49 cases (6%); and mutation was not recognized in any of the cases studied. Eight of 15 cases (53%) with decreased expression of p16 protein revealed methylation of the p16 INK4a gene promoter. Promoter hypermethylation correlated closely with decreased expression and poor prognosis ( p = 0.0014 and p = 0.0088, respectively). These results suggest that decreased expression of p16 protein can be considered as an independent reliable prognostic parameter in patients with soft tissue LMS. Furthermore, promoter methylation was more frequent than either homozygous deletion or mutation in this tumour, and promoter methylation was also shown to have a strong association with inactivation of the p16 INK4a gene. Copyright © 2003 John Wiley & Sons, Ltd.