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Background  Hypermethylation of DNA is an epigenetic alteration commonly found in colorectal cancer (CRC) and can also be detected in blood samples of cancer patients. Methylation of the genes helicase-like transcription factor ( HLTF ) and hyperplastic polyposis 1 ( HPP1 ) have been proposed as prognostic, and neurogenin 1 ( NEUROG1 ) as diagnostic biomarker. However the underlying mechanisms leading to the release of these genes are unclear. This study aimed at examining the possible correlation of the presence of methylated genes  NEUROG1 ,  HLTF  and  HPP1  in serum with tissue breakdown as a possible mechanism using serum lactate dehydrogenase (LDH) as a surrogate marker. Additionally the prognostic impact of these markers was examined.    Methods  Pretherapeutic serum samples from 259 patients from all cancer stages were analyzed. Presence of hypermethylation of the genes  HLTF ,  HPP1 , and  NEUROG1  was examined using methylation-specific quantitative PCR (MethyLight). LDH was determined using an UV kinetic test.    Results  Hypermethylation of  HLTF  and  HPP1  was detected significantly more often in patients with elevated LDH levels (32% vs. 12% [p = 0.0005], and 68% vs. 11% [p < 0.0001], respectively). Also, higher LDH values correlated with a higher percentage of a fully methylated reference in a linear fashion (Spearman correlation coefficient 0.18 for  HLTF  [p = 0.004]; 0.49 [p < .0001] for  HPP1 ). No correlation between methylation of  NEUROG1  and LDH was found in this study. Concerning the clinical characteristics, high levels of LDH as well as methylation of  HLTF  and  HPP1  were significantly associated with larger and more advanced stages of CRC. Accordingly, these three markers were correlated with significantly shorter survival in the overall population. Moreover, all three identified patients with a worse prognosis in the subgroup of stage IV patients.    Conclusions  We were able to provide evidence that methylation of  HLTF  and especially  HPP1  detected in serum is strongly correlated with cell death in CRC using LDH as surrogate marker. Additionally, we found that prognostic information is given by both  HLTF  and  HPP1  as well as LDH. In sum, determining the methylation of  HLTF  and  HPP1  in serum might be useful in order to identify patients with more aggressive tumors.

Circulating cell-free methylated DNA and lactate dehydrogenase release in colorectal cancer