Dynamics of LINE-1 retrotransposon methylation levels in circulating DNA from lung cancer patients undergoing antitumor therapy |
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| Authors: | A. A. Ponomaryova N. V. Cherdyntseva A. A. Bondar A. Y. Dobrodeev A. A. Zavyalov S. A. Tuzikov V. V. Vlassov E. L. Choinzonov P. P. Laktionov E. Y. Rykova |
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| Affiliation: | 1.Tomsk National Center for Medical Research,Russian Academy of Sciences,Tomsk,Russia;2.Institute of Chemical Biology and Fundamental Medicine,Siberian Branch of the Russian Academy of Science,Novosibirsk,Russia;3.Tomsk Polytechnical University,Tomsk,Russia;4.Тomsk State University,Tomsk,Russia;5.Meshalkin Siberian Federal Biomedical Research Center,Novosibirsk,Russia;6.Novosibirsk State Technical University,Novosibirsk,Russia |
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| Abstract: | Malignant cell transformation is accompanied with abnormal DNA methylation, such as the hypermethylation of certain gene promoters and hypomethylation of retrotransposons. In particular, the hypomethylation of the human-specific family of LINE-1 retrotransposons was observed in lung cancer tissues. It is also known that the circulating DNA (cirDNA) of blood plasma and cell-surface-bound circulating DNA (csb-cirDNA) of cancer patients accumulate tumor-specific aberrantly methylated DNA fragments, which are currently considered to be valuable cancer markers. This work compares LINE-1 retrotransposon methylation patterns in cirDNA of 16 lung cancer patients before and after treatment. CirDNA was isolated from blood plasma, and csb-cirDNA fractions were obtained by successive elution with EDTA-containing phosphate buffered saline and trypsin. Concentrations of methylated LINE-1 region 1 copies (LINE-1-met) were assayed by real-time methylation-specific PCR. LINE-1 methylation levels were normalized to the concentration of LINE-1 region 2, which was independent of the methylation status (LINE-1-Ind). The concentrations of LINE-1-met and LINE-1-Ind in csb-cirDNA of lung cancer patients exhibited correlations before treatment (r = 0.54), after chemotherapy (r = 0.72), and after surgery (r = 0.83) (P < 0.05, Spearman rank test). In the total group of patients, the level of LINE-1 methylation (determined as the LINE-1-met/LINE-1-Ind ratio) was shown to increase significantly during the follow-up after chemotherapy (P < 0.05, paired t test) and after surgery compared to the level of methylation before treatment (P < 0.05, paired t test). The revealed association between the level of LINE-1 methylation and the effect of antitumor therapy was more pronounced in squamous cell lung cancer than in adenocarcinoma (P < 0.05 and P > 0.05, respectively). These results suggest a need for the further investigation of dynamic changes in levels of LINE-1 methylation depending on the antitumor therapy. |
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