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

Abstract

BackgroundHypermethylation 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.MethodsPretherapeutic 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.ResultsHypermethylation 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.ConclusionsWe 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.

Systemic Immune-inflammation Index, Based on Platelet Counts and Neutrophil-Lymphocyte Ratio, Is Useful for Predicting Prognosis in Small Cell Lung Cancer

“…LDH can be released during tissue damage and is involved in tumor initiation and metabolism. Numerous studies have shown that LDH activity is an indicator of metastatic risk and could be an important prognostic factor in a variety of cancers (Weide et al 2013;Cetin et al 2014;Philipp et al 2014;Ulas et al 2014;Liu et al 2015). The use of LDH as a prognostic factor in SCLC has also been demonstrated over recent decades (Tas et al 2001;Bremnes et al 2003;Hermes et al 2010).…”

The value of prognostic factors in Chinese patients with small cell lung cancer: A retrospective study of 999 patients

“…[19][20][21][22][23][24][25] Furthermore, several studies have suggested that elevated LDH levels are correlated with radio/chemoresistance in several malignancies. LDH is essential for anaerobic glycolysis and converts pyruvate to lactate reversibly.…”

The helicase-like transcription factor (HLTF) in cancer: loss of function or oncomorphic conversion of a tumor suppressor?

“…HLTF promoter methylation is rarely observed in normal colon tissue (3.0-10.2 %). However, it is increased in colon adenoma (25.7-68.5 %) [13,56] and remains stable or slightly increased in invasive carcinomas (34.3-41.4 %), independently of tumor stage [13,[55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70] ( Table 3). HLTF promoter hypermethylation was analyzed in association with the methylation of other genes.…”

“…Several groups detected HLTF promoter hypermethylation in serum/plasma of patients with colon cancer (Table 3) [62][63][64][65][66][67][68]. The purpose of analyzing gene methylation in cancer patients is for use as a biomarker to predict outcomes, including survival and disease recurrence.…”