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Identification of Serial DNA Methylation Changes in the Blood Samples of Patients with Lung Cancer

  • Moon, Da Hye (Department of Internal Medicine, Kangwon National University Hospital) ;
  • Kwon, Sung Ok (Biomedical Research Institute, Kangwon National University Hospital) ;
  • Kim, Woo Jin (Department of Internal Medicine, Kangwon National University Hospital) ;
  • Hong, Yoonki (Department of Internal Medicine, Kangwon National University Hospital)
  • Received : 2018.05.06
  • Accepted : 2018.07.31
  • Published : 2019.04.30

Abstract

Background: The development of lung cancer results from the interaction between genetic mutations and dynamic epigenetic alterations, although the exact mechanisms are not completely understood. Changes in DNA methylation may be a promising biomarker for early detection and prognosis of lung cancer. We evaluated the serial changes in genome-wide DNA methylation patterns in blood samples of lung cancer patients. Methods: Blood samples were obtained for three consecutive years from three patients (2 years before, 1 year before, and after lung cancer detection) and from three control subjects (without lung cancer). We used the MethylationEPIC BeadChip method, which covers the 850,000 bp cytosine-phosphate-guanine (CpG) site, to conduct an epigenome-wide analysis. Significant differentially methylated regions (DMRs) were identified using p-values <0.05 in a correlation test identifying serial methylation changes and serial increase or decrease in ${\beta}$ value above 0.1 for three consecutive years. Results: We found three significant CpG sites with differentially methylated ${\beta}$ values and 7,105 CpG sites with significant correlation from control patients without lung cancer. However, there were no significant DMRs. In contrast, we found 11 significant CpG sites with differentially methylated ${\beta}$ values and 10,562 CpG sites with significant correlation from patients with lung cancer. There were two significant DMRs: cg21126229 (RNF212) and cg27098574 (BCAR1). Conclusion: This study revealed DNA methylation changes that might be implicated in lung cancer development. The DNA methylation changes may be the possible candidate target regions for the early detection and prevention of lung cancer.

Keywords

References

  1. Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Dicker D, Pain A, Hamavid H, Moradi-Lakeh M, et al. The global burden of cancer 2013. JAMA Oncol 2015;1:505-27. https://doi.org/10.1001/jamaoncol.2015.0735
  2. Park JY, Jang SH. Epidemiology of lung cancer in Korea: recent trends. Tuberc Respir Dis 2016;79:58-69. https://doi.org/10.4046/trd.2016.79.2.58
  3. Shin A, Oh CM, Kim BW, Woo H, Won YJ, Lee JS. Lung cancer epidemiology in Korea. Cancer Res Treat 2017;49:616-26. https://doi.org/10.4143/crt.2016.178
  4. Balgkouranidou I, Liloglou T, Lianidou ES. Lung cancer epigenetics: emerging biomarkers. Biomark Med 2013;7:49-58. https://doi.org/10.2217/bmm.12.111
  5. Devarakonda S, Morgensztern D, Govindan R. Genomic alterations in lung adenocarcinoma. Lancet Oncol 2015;16:e342-51. https://doi.org/10.1016/S1470-2045(15)00077-7
  6. Esteller M. Non-coding RNAs in human disease. Nat Rev Genet 2011;12:861-74. https://doi.org/10.1038/nrg3074
  7. Zhang Y. Recent progress in the epigenetics and chromatin field. Cell Res 2011;21:373-4. https://doi.org/10.1038/cr.2011.33
  8. Ansari J, Shackelford RE, El-Osta H. Epigenetics in non-small cell lung cancer: from basics to therapeutics. Transl Lung Cancer Res 2016;5:155-71. https://doi.org/10.21037/tlcr.2016.02.02
  9. Mehta A, Dobersch S, Romero-Olmedo AJ, Barreto G. Epigenetics in lung cancer diagnosis and therapy. Cancer Metastasis Rev 2015;34:229-41. https://doi.org/10.1007/s10555-015-9563-3
  10. Hong Y, Ji W, An S, Han SS, Lee SJ, Kim WJ. Sex differences of COPD phenotypes in nonsmoking patients. Int J Chron Obstruct Pulmon Dis 2016;11:1657-62. https://doi.org/10.2147/COPD.S108343
  11. Oken MM, Hocking WG, Kvale PA, Andriole GL, Buys SS, Church TR, et al. Screening by chest radiograph and lung cancer mortality: the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized trial. JAMA 2011;306:1865-73. https://doi.org/10.1001/jama.2011.1591
  12. National Lung Screening Trial Research Team, Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395-409. https://doi.org/10.1056/NEJMoa1102873
  13. van der Aalst CM, Ten Haaf K, de Koning HJ. Lung cancer screening: latest developments and unanswered questions. Lancet Respir Med 2016;4:749-61. https://doi.org/10.1016/S2213-2600(16)30200-4
  14. Hubers AJ, Brinkman P, Boksem RJ, Rhodius RJ, Witte BI, Zwinderman AH, et al. Combined sputum hypermethylation and eNose analysis for lung cancer diagnosis. J Clin Pathol 2014;67:707-11. https://doi.org/10.1136/jclinpath-2014-202414
  15. Kneip C, Schmidt B, Seegebarth A, Weickmann S, Fleischhacker M, Liebenberg V, et al. SHOX2 DNA methylation is a biomarker for the diagnosis of lung cancer in plasma. J Thorac Oncol 2011;6:1632-8. https://doi.org/10.1097/JTO.0b013e318220ef9a
  16. Ahrendt SA, Chow JT, Xu LH, Yang SC, Eisenberger CF, Esteller M, et al. Molecular detection of tumor cells in bronchoalveolar lavage fluid from patients with early stage lung cancer. J Natl Cancer Inst 1999;91:332-9. https://doi.org/10.1093/jnci/91.4.332
  17. Xiao P, Chen JR, Zhou F, Lu CX, Yang Q, Tao GH, et al. Methylation of P16 in exhaled breath condensate for diagnosis of non-small cell lung cancer. Lung Cancer 2014;83:56-60. https://doi.org/10.1016/j.lungcan.2013.09.008
  18. Brock MV, Hooker CM, Ota-Machida E, Han Y, Guo M, Ames S, et al. DNA methylation markers and early recurrence in stage I lung cancer. N Engl J Med 2008;358:1118-28. https://doi.org/10.1056/NEJMoa0706550
  19. Sandoval J, Mendez-Gonzalez J, Nadal E, Chen G, Carmona FJ, Sayols S, et al. A prognostic DNA methylation signature for stage I non-small-cell lung cancer. J Clin Oncol 2013;31:4140-7. https://doi.org/10.1200/JCO.2012.48.5516
  20. Hsu HS, Chen TP, Hung CH, Wen CK, Lin RK, Lee HC, et al. Characterization of a multiple epigenetic marker panel for lung cancer detection and risk assessment in plasma. Cancer 2007;110:2019-26. https://doi.org/10.1002/cncr.23001
  21. Belinsky SA, Grimes MJ, Casas E, Stidley CA, Franklin WA, Bocklage TJ, et al. Predicting gene promoter methylation in non-small-cell lung cancer by evaluating sputum and serum. Br J Cancer 2007;96:1278-83. https://doi.org/10.1038/sj.bjc.6603721
  22. Stirzaker C, Taberlay PC, Statham AL, Clark SJ. Mining cancer methylomes: prospects and challenges. Trends Genet 2014;30:75-84. https://doi.org/10.1016/j.tig.2013.11.004
  23. Bibikova M, Le J, Barnes B, Saedinia-Melnyk S, Zhou L, Shen R, et al. Genome-wide DNA methylation profiling using Infinium(R) assay. Epigenomics 2009;1:177-200. https://doi.org/10.2217/epi.09.14
  24. Pidsley R, Zotenko E, Peters TJ, Lawrence MG, Risbridger GP, Molloy P, et al. Critical evaluation of the Illumina Methylation-EPIC BeadChip microarray for whole-genome DNA methylation profiling. Genome Biol 2016;17:208. https://doi.org/10.1186/s13059-016-1066-1
  25. Qiao H, Prasada Rao HB, Yang Y, Fong JH, Cloutier JM, Deacon DC, et al. Antagonistic roles of ubiquitin ligase HEI10 and SUMO ligase RNF212 regulate meiotic recombination. Nat Genet 2014;46:194-9. https://doi.org/10.1038/ng.2858
  26. Sandor C, Li W, Coppieters W, Druet T, Charlier C, Georges M. Genetic variants in REC8, RNF212, and PRDM9 influence male recombination in cattle. PLoS Genet 2012;8:e1002854. https://doi.org/10.1371/journal.pgen.1002854
  27. Foulkes WD. Inherited susceptibility to common cancers. N Engl J Med 2008;359:2143-53. https://doi.org/10.1056/NEJMra0802968
  28. Marsit CJ, Liu M, Nelson HH, Posner M, Suzuki M, Kelsey KT. Inactivation of the Fanconi anemia/BRCA pathway in lung and oral cancers: implications for treatment and survival. Oncogene 2004;23:1000-4. https://doi.org/10.1038/sj.onc.1207256
  29. Rosell R, Skrzypski M, Jassem E, Taron M, Bartolucci R, Sanchez JJ, et al. BRCA1: a novel prognostic factor in resected non-small-cell lung cancer. PLoS One 2007;2:e1129. https://doi.org/10.1371/journal.pone.0001129

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