Abstract
Soft tissue sarcomas (STSs) are a rare and fascinating group of diseases that can be subdivided into specific reciprocal translocations in STSs (SRTSs) and nonspecific reciprocal translocations in STSs (NRTSs). PTEN mutations are rare in STSs, suggesting that PTEN expression may be lost by alternative mechanisms such as methylation. In order to reveal whether aberrant PTEN methylation occurs in STSs, MassARRAY Spectrometry was carried to detect methylation patterns of PTEN in STSs. We evaluated methylation levels in 41 CpG sites from −2,515 to −2,186 bp (amplicon A) and −1,786 to −1,416 bp (amplicon B) relative to the translation initiation site in 110 different cases (46 cases of SRTSs, 40 cases of NRTSs, and 24 cases of normal controls). In addition, immunohistochemistry (IHC) was used to detect the loss of PTEN to determine whether PTEN alterations were responsible for decreased PTEN expression. Our data showed that expression of PTEN was diminished in 49 (57%) STSs, whereas the remaining cases (43%) were classified as high expression. Our previous results found that only 2 of 86 cases (2.3%) had a PTEN mutation suggesting that PTEN may be mainly downregulated in STSs by methylation, but not by mutation of PTEN itself. We observed that amplicon A was hypermethylated in STSs with low PTEN expression, whereas normal controls had low methylation levels (P<0.0001), which was not present in amplicon B (P>0.05), nor were there significant differences in the methylation levels in PTEN between SRTS and NRTS cases. The majority of individual CpG units within two amplicons was demonstrated to be hypermethylated. These findings indicate that PTEN hypermethylation is a common event in STSs suggesting that the inactivation of PTEN may be due to hypermethylation in the promoter of PTEN. The aberrant methylation of the CpG sites within PTEN promoter may serve as a potential candidate biomarker for STSs.
Highlights
Soft tissue sarcomas (STSs) comprise a heterogeneous group of mesenchymal tumors with wide spectrum of histologic features
We have previously shown that Phosphatase and tension homolog deleted on chromosome10 (PTEN) mutation is not a frequent event in STSs [7], suggesting that other mechanisms may be involved in activating oncogenic pathways, such as epigenetic silencing due to promoter methylation which may play an important role in the descending process of PTEN expression
The aim of the present study is to quantitatively evaluate methylation status of CpGs within the PTEN promoter using MassARRAY Spectrometry and to determine whether aberrant PTEN promoter methylation occurs in STSs, whether methylation patterns affect expression levels of PTEN in sarcoma subtypes (SRTSs and nonspecific reciprocal translocations in STSs (NRTSs)), and whether any of these alterations has potential values serving as biomarkers of STSs
Summary
Soft tissue sarcomas (STSs) comprise a heterogeneous group of mesenchymal tumors with wide spectrum of histologic features. More than 50 different subtypes have been proposed for STSs, in which malignant grades of tumors vary even among tumors of the same histologic categories [1]. Sarcoma subtypes are further classified into two groups. One group is characterized by specific and balanced translocations, which include the integration of individual translocation genes (for example, alveolar rhabdomyosarcoma has PAX3-FKHR) and the other group typically shows more extensive chromosomal rearrangements leading to recurrent, but non-specific, chromosomal gains or losses [2]. Understanding the molecular pathogenesis of STSs may provide clues in developing therapeutic regimens for STSs. little information is available for STSs at molecular level in comparison with common cancers
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