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DNA hypermethylation is frequently found in colorectal cancer (CRC). Methylation of helicase-like transcription factor (HLTF) and hyperplastic polyposis 1 (HPP1) are potential and carcinoembryonic antigen (CEA) is an established prognostic factor in serum of patients with CRC. The aim of this study was to perform a direct comparison of the prognostic roles of these markers. Methylation status of HLTF and HPP1 was examined in pretherapeutic sera of 311 patients with CRC and matched primary tissues of 54 stage IV patients using methylation-specific quantitative PCR. CEA was determined using an immunoenzymometric assay. Methylation of HLTF and HPP1 DNA in serum significantly correlated with tumor size, stage, grade and metastatic disease. HPP1 methylation correlated with nodal status. Overall survival was shortened in case of methylation of HLTF or HPP1 or elevated levels of CEA (p< 0.0001 for all). In stage IV, patients survival was impaired if HLTF (p= 0.0005) or HPP1 (p= 0.0003) were methylated or CEA was above the median of 27 ng/ml (p= 0.002). Multivariate analysis revealed that methylation of HLTF [hazard ratio (HR) 1.8,p= 0.0438], HPP1 (HR 1.6,p= 0.0495) and CEA >27 ng/ml (HR 1.7,p= 0.0317) were independent prognostic factors in stage IV. The combination of any two or all three of these factors outperformed each marker on its own. In conclusion, the presence of methylated DNA of the genes HLTF or HPP1 in serum are independent prognostic factors in metastasized CRC. Prospective validation is required to determine their usefulness in clinical routine along with the established marker CEA.