Clinical significance of DNA methylation mRNA levels of TET family members in colorectal cancer

PURPOSE: Ten eleven translocation (TET) enzyme activity is essential for active DNA demethylation in biological processes, and their altered expression has been observed in various malignancies. Therefore, we investigated DNA methylation and mRNA levels of all TETs in colorectal cancer (CRC) patients. METHODS: TET mRNA levels were evaluated using quantitative RT-PCR in primary cancerous and histopathologically unchanged colorectal tissues from patients who underwent radical surgical colon resection (n = 113). DNA methylation levels of the TET CpG island were assessed using bisulfite DNA sequencing and high-resolution melting analysis. RESULTS: We found reduced transcript levels of TET1, TET2 and TET3 in cancerous tissue compared with their histopathologically unchanged counterparts (p = 0.000011; p = 0.000001; p = 0.00031, respectively). Importantly, multivariate Cox regression analysis revealed favorable overall survival (OS) and disease-free survival (DFS) outcomes for patients with high TET2 mRNA levels in histopathologically unchanged tissue (HR(OS) = 0.091, 95 % CI 0.011–0.77, p = 0.028; HR(DFS) = 0.21, 95 % CI 0.04–1.06, p = 0.059). Moreover, we found no DNA methylation in the TET2 and TET3 promoter regions in cancerous and histopathologically unchanged tissue. In contrast, we reported TET1 DNA hypermethylation in a small fraction of patients (n = 12/113). CONCLUSION: To best of our knowledge, our study is the first to investigate TET mRNA levels in a cohort of CRC patients and correlate them with patients’ prognosis. Present study provides the evidence that TET2 mRNA expression may be an independent prognostic factor for disease recurrence and outcome. Additionally, our findings initially indicate the importance of DNA methylation in regulating TET1 expression. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00432-014-1901-2) contains supplementary material, which is available to authorized users.