# Reduced 5-hydroxymethylcytosine due to TET2 downregulation is associated with chondrosarcoma progression

## TL;DR

Low levels of 5-hydroxymethylcytosine (5hmC) are linked to worse outcomes in chondrosarcoma, possibly due to TET2 downregulation and activation of cancer-related pathways.

## Contribution

This study identifies 5hmC as a potential prognostic marker in chondrosarcoma and links its reduction to TET2 downregulation and oncogenic pathway activation.

## Key findings

- Low 5hmC levels are significantly associated with worse prognosis in chondrosarcoma.
- TET2 downregulation leads to reduced 5hmC levels and activation of MAPK and PI3K-Akt/mTOR pathways.
- Higher levels of p-MEK, p-ERK, p-Akt, and p-mTOR are observed in the low 5hmC group.

## Abstract

Chondrosarcoma (CS) is the second most common malignant bone tumor, known for its poor prognosis, high recurrence rate, and potential for metastasis. Current prognostic predictive methods rely heavily on histological grading, underscoring the need for additional markers. DNA methylation, particularly the role of 5-hydroxymethylcytosine (5hmC), has emerged as a promising prognostic indicator in various malignancies. This study aimed to investigate the relationship between 5hmC expression levels and CS prognosis. Additionally, RNA analysis was performed to identify differentially expressed genes associated with low 5hmC levels. The findings indicate that low 5hmC levels were significantly linked to a worse prognosis and decreased ten-eleven translocation 2 (TET2). Furthermore, the reduction in 5hmC levels was linked to the activation of oncogenic signaling pathways, such as MAPK and PI3K-Akt/mTOR. Immunohistochemical markers such as phospho-MEK (p-MEK), p-ERK, p-Akt, and p-mTOR were higher in the 5hmC low group than in the high group. These findings suggest that 5hmC levels not only reflect the epigenetic state of CS tumors but also hold promise as a valuable prognostic marker for identifying patients at heightened risk of adverse outcomes. Furthermore, TET2 downregulation results in a decrease in 5hmC levels with subsequent activation of the MAPK and PI3K/Akt/mTOR pathways.

The online version contains supplementary material available at 10.1038/s41598-025-25820-9.