Skip to main content
SpringerLink
Log in

Dynamics of LINE-1 retrotransposon methylation levels in circulating DNA from lung cancer patients undergoing antitumor therapy

  • Molecular Cell Biology
  • Published:
Molecular Biology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

AC:

adenocarcinoma

cirDNA:

circulating DNA

csb-cirDNA:

cell surface-bound circulating DNA

LC:

lung cancer

NSCLC:

non-small cell lung cancer

SCLC:

squamous cell lung cancer

GE:

genome equivalent

References

  1. Esteller M. 2008. Epigenetics in cancer. N. Engl. J. Med. 358, 1148–1159.

    Article  CAS  PubMed  Google Scholar 

  2. Duffy M.J., Napieralski R., Martens J.W., Span P.N., Spyratos F., Sweep F.C., Brunner N., Foekens J.A., Schmitt M. 2009. Methylated genes as new cancer biomarkers. Eur. J. Cancer. 45, 335–346.

    Article  CAS  PubMed  Google Scholar 

  3. Bergman Y., Cedar H. 2013. DNA methylation dynamics in health and disease. Nat. Struct. Mol. Biol. 20, 274–281.

    Article  CAS  PubMed  Google Scholar 

  4. Pal’tsev M.A., Zaletaev D.V. 2009. Sistemy geneticheskikh i epigeneticheskikh markerov v diagnostike zlokachestvennykh zabolevanii (Systems of Genetic and Epigenetic Markers in the Diagnosis of Malignant Diseases). Moscow: Meditsina.

    Google Scholar 

  5. Rykova E.Y., Morozkin E.S., Ponomaryova A.A., Loseva E.M., Zaporozhchenko I.A., Cherdyntseva N.V., Vlassov V.V., Laktionov P.P. 2012. Cell-free and cellbound circulating nucleic acid complexes: Mechanisms of generation, concentration and content. Expert Opin. Biol. Ther. 12, S141–S153.

    Article  CAS  PubMed  Google Scholar 

  6. Ponomaryova A.A., Rykova E.Y., Cherdyntseva N.V., Skvortsova T.E., Dobrodeev A.Y., Zav’yalov A.A., Bryzgalov L.O., Tuzikov S.A., Vlassov V.V., Laktionov P.P. 2013. Potentialities of aberrantly methylated circulating DNA for diagnostics and post-treatment follow-up of lung cancer patients. Lung Cancer. 81, 397–403.

    Article  PubMed  Google Scholar 

  7. Schwarzenbach H., Nishida N., Calin G.A., Pantel K. 2014. Clinical relevance of circulating cell-free microRNAs in cancer. Nat. Rev. Clin. Oncol. 11, 145–156.

    Article  CAS  PubMed  Google Scholar 

  8. Cedar H., Bergman Y. 2012. Programming of DNA methylation patterns. Annu. Rev. Biochem. 81, 97–117.

    Article  CAS  PubMed  Google Scholar 

  9. Fedorov A.V. 2008. Transcriptional regulation of LINE1 retrotransposons of mammals. Tsitologiya. 50, 1011–1022.

    CAS  Google Scholar 

  10. Ikeda K., Shiraishi K., Eguchi A., Shibata H., Yoshimoto K., Mori T., Baba Y., Baba H., Suzuki M. 2013. Long interspersed nucleotide element 1 hypomethylation is associated with poor prognosis of lung adenocarcinoma. Ann. Thorac. Surg. 96, 1790–1794.

    Article  PubMed  Google Scholar 

  11. Rhee Y.Y., Lee T.H., Song Y.S., Wen X., Kim H., Jheon S., Lee C.T., Kim J., Cho N.Y., Chung J.H., Kang G.H. 2015. Prognostic significance of promoter CpG island hypermethylation and repetitive DNA hypomethylation in stage I lung adenocarcinoma. Virchows Arch. 466, 675–683.

    Article  CAS  PubMed  Google Scholar 

  12. Ramzy I.I., Omran D.A., Hamad O., Shaker O., Abboud A. 2011. Evaluation of serum LINE-1 hypomethylation as a prognostic marker for hepatocellular carcinoma. Arab. J. Gastroenterol. 12, 139–142.

    Article  CAS  PubMed  Google Scholar 

  13. Hoshimoto S., Kuo C.T., Chong K.K., Takeshima T.L., Takei Y., Li M.W., Huang S.K., Sim M.S., Morton D.L., Hoon D.S. 2012. AIM1 and LINE-1 epigenetic aberrations in tumor and serum relate to melanoma progression and disease outcome. J. Invest. Dermatol. 132, 1689–1697.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ponomaryova A.A., Rykova E.Y., Cherdyntseva N.V., Bondar A.A., Dobrodeev A.Y., Zavyalov A.A., Tuzikov S.A., Bryzgalov L.O., Merkulova T.I., Vlassov V.V., Laktionov P.P. 2015. Epigenetic “probes” for lung cancer monitoring: Line-1 methylation pattern in bloodcirculating DNA. Russ. J. Genetics Appl. Res. 19, 144–150.

    Google Scholar 

  15. Aparicio A., North B., Barske L., Wang X., Bollati V., Weisenberger D., Yoo C., Tannir N., Horne E., Groshen S., Jones P., Yang A., Issa J.P. 2009. LINE-1 methylation in plasma DNA as a biomarker of activity of DNA methylation inhibitors in patients with solid tumors. Epigenetics. 4, 176–184.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bryzgunova O., Laktionov P., Skvortsova T., Bondar A., Morozkin E., Lebedeva A., Krause H., Miller K., Vlassov V. 2013. Efficacy of bisulfite modification and recovery of human of genomic and circulating DNA using commercial kits. Eur. J. Mol. Biol. 1, 1–8.

    Google Scholar 

  17. Weisenberger D.J., Campan M., Long T.I., Kim M., Woods C., Fiala E., Melanie Ehrlich M., Laird P.W. 2005. Analysis of repetitive element DNA methylation by MethyLight. Nucleic Acids Res. 33, 6823–6836.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Qin T., Si J., Raynal N.J., Wang X., Gharibyan V., Ahmed S., Hu X., Jin C., Lu Y., Shu J., Estecio M.R., Jelinek J., Issa J.P. 2015. Epigenetic synergy between decitabine and platinum derivatives. Clin. Epigenetics. 7, 97.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Boulikas T., Tsogas I. 2008. Microtubule-targeted antitumor drugs: Chemistry, mechanisms and nanoparticle formulations. Gene Ther. Mol. Biol. 12, 343–387.

    Google Scholar 

  20. Davidson M.R., Gazdar A.F., Clarke B.E. 2013. The pivotal role of pathology in the management of lung cancer. J. Thorac. Dis. 5, S463–S478.

    PubMed  PubMed Central  Google Scholar 

  21. Suzuki M., Shiraishi K., Eguchi A., Ikeda K., Mori T., Yoshimoto K., Ohba Y., Yamada T., Ito T., Baba Y., Baba H. 2013. Aberrant methylation of LINE-1, SLIT2, MAL and IGFBP7 in non-small cell lung cancer. Oncol. Rep. 29, 1308–1314.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Lockwood W.W. Wilson I.M., Coe B.P., Chari R., Pikor L.A., Thu K.L., Solis L.M., Nunez M.I., Behrens C., Yee J., English J., Murray N., Tsao M.S., Minna J.D., Gazdar A.F., et al. 2012. Divergent genomic and epigenomic landscapes of lung cancer subtypes underscore the selection of different oncogenic pathways during tumor development. PLoS ONE. 7, e37775.

    Article  Google Scholar 

  23. Chari R., Lonergan K.M., Ng R.T., MacAulay C., Lam W.L., Lam S. 2007. Effect of active smoking on the human bronchial epithelium transcriptome. BMC Genomics. 8, 297.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Sun S., Schiller J.H., Gazdar A.F. 2007. Lung cancer in never smokers: A different disease. Nat. Rev. Cancer. 7, 778–790.

    Article  CAS  PubMed  Google Scholar 

  25. Murata A., Baba Y., Watanabe M., Shigaki H., Miyake K., Ishimoto T., Iwatsuki M., Iwagami S., Sakamoto Y., Miyamoto Y., Yoshida N., Nosho K., Baba H. 2013. Methylation levels of LINE-1 in primary lesion and matched metastatic lesions of colorectal cancer. Br. J. Cancer. 109, 408–415.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Tomsk National Center for Medical Research, Russian Academy of Sciences, Tomsk, 634009, Russia

    A. A. Ponomaryova, N. V. Cherdyntseva, A. Y. Dobrodeev, A. A. Zavyalov, S. A. Tuzikov & E. L. Choinzonov

  2. Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Science, Novosibirsk, 630117, Russia

    A. A. Bondar, V. V. Vlassov, P. P. Laktionov & E. Y. Rykova

  3. Tomsk Polytechnical University, Tomsk, 634034, Russia

    A. A. Ponomaryova

  4. Тomsk State University, Tomsk, 634050, Russia

    N. V. Cherdyntseva

  5. Meshalkin Siberian Federal Biomedical Research Center, Novosibirsk, 630055, Russia

    P. P. Laktionov

  6. Novosibirsk State Technical University, Novosibirsk, 630073, Russia

    E. Y. Rykova

Authors
  1. A. A. Ponomaryova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N. V. Cherdyntseva
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. A. Bondar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Y. Dobrodeev
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. A. Zavyalov
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S. A. Tuzikov
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. V. V. Vlassov
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. E. L. Choinzonov
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. P. P. Laktionov
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. E. Y. Rykova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. Y. Rykova.

Additional information

Original Russian Text © 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, 2017, published in Molekulyarnaya Biologiya, 2017, Vol. 51, No. 4, pp. 622–628.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ponomaryova, A.A., Cherdyntseva, N.V., Bondar, A.A. et al. Dynamics of LINE-1 retrotransposon methylation levels in circulating DNA from lung cancer patients undergoing antitumor therapy. Mol Biol 51, 549–554 (2017). https://doi.org/10.1134/S0026893317040148

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0026893317040148

Keywords

Search

Navigation