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Genetic and epigenetic alterations of the PTEN gene in soft tissue sarcomas
Ken-ichi Kawaguchi1, Yoshinao Oda, Tsuyoshi Saito
1Department of Anatomic Pathology, Pathological sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Abstract:
The PTEN/MMAC1 ( PTEN ) gene was identified as a tumor suppressor gene encoding a cytoplasmic protein that controls cellular processes. To investigate the potential role and the alteration of the PTEN gene in soft tissue sarcomas (STSs), we searched for homozygous deletion and promoter hypermethylation in a series of 48 STSs that was composed of malignant fibrous histiocytoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, including 2 cases with a mutation that we previously reported; differential polymerase chain reaction and methylation-specific polymerase chain reaction, respectively, were used for the analyses. Furthermore, to determine whether PTEN gene alterations are involved in the down-regulation of PTEN expression, we examined the expression of PTEN protein in 38 cases in which paraffin-embedded tissues were available for immunohistochemical analysis. In addition to our previous results showing that 2 (4%) of 51 cases had a PTEN mutation, promoter methylation was recognized in 6 (13%) of 48 cases, and homozygous deletion was detected in 1 (2%) of 48 cases in the current study. Of 6 cases with promoter methylation of PTEN gene, 5 were malignant peripheral nerve sheath tumor. Decreased expression of PTEN protein was recognized in 11 (29%) of 38 STS cases. Of 9 cases with PTEN alterations (6 cases with promoter methylation, 2 with mutation, and 1 with homozygous deletion), 3 (33%) showed decreased expression of PTEN protein. Furthermore, decreased expression of the PTEN gene showed a statistically significant correlation with high MIB-1 labeling index in 38 STS cases examined ( P = .0441). In conclusion, promoter methylation and homozygous deletion of the PTEN gene were found to be relatively rare events in cases of STS, as is mutation of the gene. Of 9 cases with a PTEN alteration, 3 (33%) showed a decrease in PTEN expression, indicating that PTEN gene alterations seem to play a minor role in the inactivation of PTEN in these tumors. Furthermore, although a further detailed analysis of a larger number of cases is still necessary, the present results suggest that PTEN expression may be a useful indicator of cell proliferation in patients with STS.
Insights
PTEN gene alterations like promoter methylation and deletion are rare in soft tissue sarcomas (STSs). While PTEN alterations occur, they play a minor role in PTEN inactivation and may indicate cell proliferation in STSs.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The PTEN/MMAC1 (PTEN) gene is a crucial tumor suppressor involved in cellular process control.
- Understanding PTEN gene alterations in soft tissue sarcomas (STSs) is vital for cancer research.
- Previous studies have identified PTEN mutations in some STS cases.
Purpose of the Study:
- To investigate the frequency and role of PTEN gene alterations, including homozygous deletion and promoter hypermethylation, in soft tissue sarcomas (STSs).
- To determine if PTEN gene alterations contribute to decreased PTEN expression in STSs.
- To explore the correlation between PTEN expression and tumor cell proliferation markers like MIB-1.
Main Methods:
- Analysis of 48 STS cases for homozygous deletion using differential polymerase chain reaction (PCR).
- Detection of PTEN promoter hypermethylation via methylation-specific PCR in 48 STS cases.
- Immunohistochemical analysis of PTEN protein expression in 38 STS cases.
Main Results:
- PTEN mutations were found in 4% of cases (previously reported).
- Promoter methylation occurred in 13% of STSs, predominantly in malignant peripheral nerve sheath tumors.
- Homozygous deletion was detected in 2% of STSs.
- Decreased PTEN protein expression was observed in 29% of cases.
- PTEN alterations (mutation, methylation, deletion) were associated with decreased PTEN expression in 33% of affected cases.
- Decreased PTEN expression significantly correlated with a high MIB-1 labeling index (P = .0441).
Conclusions:
- PTEN gene promoter methylation and homozygous deletion are infrequent events in STSs.
- PTEN gene alterations appear to play a limited role in PTEN inactivation in these tumors.
- Reduced PTEN expression shows a significant correlation with increased cell proliferation in STSs, suggesting PTEN's potential as a prognostic indicator.
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