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Gastric Cancer

, Volume 22, Issue 1, pp 37–47 | Cite as

Combinatory low methylation statuses of SAT-α and L1 are associated with shortened survival time in patients with advanced gastric cancer

  • Younghoon Kim
  • Xianyu Wen
  • Seorin Jeong
  • Nam-Yun Cho
  • Woo Ho Kim
  • Gyeong Hoon KangEmail author
Original Article
  • 189 Downloads

Abstract

Background

L1 and SAT-α are repetitive DNA elements that undergo demethylation in association with cancerization. Unlike L1 hypomethaylation, nothing is known regarding the prognostic implication of SAT-α hypomethylation alongside L1 hypomethaylaton in gastric cancers.

Methods

Formalin-fixed paraffin-embedded samples from 492 cases of advanced gastric cancer were analyzed to determine their L1 and SAT-α methylation status using pyrosequencing methylation assay.

Results

L1 and SAT-α methylation statuses were correlated with clinicopathological parameters, including survival. L1 or SAT-α methylation levels were lower in gastric cancers with venous invasion or nodal metastasis than those without. L1 methylation was lower in gastric cancers with lymphatic emboli than in those with no lymphatic emboli, but was higher in gastric cancers with perineural invasion than in those with no perineural invasion. Multivariate survival analysis revealed that both tumoral L1 and SAT-α hypomethylations were found to correlate independently with OS (HR = 1.477; 95% CI 1.079–2.021 and HR = 1.394; 95% CI 1.011–1.922, respectively) and RFS (HR = 1.477; 95% CI 1.090–2.001 and HR = 1.516; 95% CI 1.106–2.078, respectively). Combined L1 and SAT-α hypomethylation turned out to correlate independently with OS (HR = 2.003; 95% CI 1.268–3.164) and RFS (HR = 2.226; 95% CI 1.411–3.510).

Conclusion

Not only tumoral L1 hypomethylation, but also tumoral SAT-α hypomethylation was found to be independent prognostic parameters in patients with advanced gastric cancer. SAT-α methylation status can be used to further divide gastric cancers with L1 hypomethylation into subsets of gastric cancers with better and worse prognosis.

Keywords

DNA methylation Gastric cancer L1 element Prognosis Satellite alpha 

Notes

Acknowledgements

This work was supported by a grant from the Basic Science Research Program through the National Research Foundation (NRF) funded by the Korea Ministry of Science, ICT and Future Planning (2011-0030049; 2016M3A9B6026921) and a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Korean Ministry of Health and Welfare (HI14C1277).

Compliance with ethical standards

Ethical standards

This study was approved by Seoul National University Hospital Institute Review of Board, which waived the requirement to obtain informed consent (IRB No. 1312-051-542) and was conducted in accordance with the Declaration of Helsinki.

Conflict of interest

The authors have declared that no competing interests exists.

Supplementary material

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Supplementary Figure 1. Correlation between L1 methylation level and age according to histological type and sex (TIF 414 KB)
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Supplementary Figure 2. Correlation between SAT-α methylation level and age according to histological type and sex (TIF 434 KB)

References

  1. 1.
    Cordaux R, Batzer MA. The impact of retrotransposons on human genome evolution. Nat Rev Genet. 2009;10(10):691–703.  https://doi.org/10.1038/nrg2640.CrossRefGoogle Scholar
  2. 2.
    Woodcock DM, Lawler CB, Linsenmeyer ME, Doherty JP, Warren WD. Asymmetric methylation in the hypermethylated CpG promoter region of the human L1 retrotransposon. J Biol Chem. 1997;272(12):7810–6.CrossRefGoogle Scholar
  3. 3.
    Montoya-Durango DE, Ramos KS. L1 retrotransposon and retinoblastoma: molecular linkages between epigenetics and cancer. Curr Mol Med. 2010;10(5):511–21.CrossRefGoogle Scholar
  4. 4.
    Valgardsdottir R, Chiodi I, Giordano M, Rossi A, Bazzini S, Ghigna C, et al. Transcription of satellite III non-coding RNAs is a general stress response in human cells. Nucleic Acids Res. 2008;36(2):423–34.CrossRefGoogle Scholar
  5. 5.
    Bouzinba-Segard H, Guais A, Francastel C. Accumulation of small murine minor satellite transcripts leads to impaired centromeric architecture and function. Proc Natl Acad Sci USA. 2006;103(23):8709–14.CrossRefGoogle Scholar
  6. 6.
    Weisenberger DJ, Campan M, Long TI, Kim M, Woods C, Fiala E, et al. Analysis of repetitive element DNA methylation by MethyLight. Nucleic Acids Res. 2005;33(21):6823–36.CrossRefGoogle Scholar
  7. 7.
    Park SY, Yoo EJ, Cho NY, Kim N, Kang GH. Comparison of CpG island hypermethylation and repetitive DNA hypomethylation in premalignant stages of gastric cancer, stratified for Helicobacter pylori infection. J Pathol. 2009;219(4):410–6.CrossRefGoogle Scholar
  8. 8.
    Bae JM, Shin SH, Kwon HJ, Park SY, Kook MC, Kim YW, et al. ALU and LINE-1 hypomethylations in multistep gastric carcinogenesis and their prognostic implications. Int J Cancer. 2012;131(6):1323–31.CrossRefGoogle Scholar
  9. 9.
    Shigaki H, Baba Y, Watanabe M, Murata A, Iwagami S, Miyake K, et al. LINE-1 hypomethylation in gastric cancer, detected by bisulfite pyrosequencing, is associated with poor prognosis. Gastric Cancer. 2013;16(4):480–7.CrossRefGoogle Scholar
  10. 10.
    Song YS, Kim Y, Cho NY, Yang HK, Kim WH, Kang GH. Methylation status of long interspersed element-1 in advanced gastric cancer and its prognostic implication. Gastric Cancer. 2016;19(1):98–106.CrossRefGoogle Scholar
  11. 11.
    Wen X, Jeong S, Kim Y, Bae JM, Cho NY, Kim JH, et al. Improved results of LINE-1 methylation analysis in formalin-fixed, paraffin-embedded tissues with the application of a heating step during the DNA extraction process. Clin Epigenet. 2017;9:1.CrossRefGoogle Scholar
  12. 12.
    Choi SH, Worswick S, Byun HM, Shear T, Soussa JC, Wolff EM, et al. Changes in DNA methylation of tandem DNA repeats are different from interspersed repeats in cancer. Int J Cancer. 2009;125(3):723–9.CrossRefGoogle Scholar
  13. 13.
    Tournier B, Chapusot C, Courcet E, Martin L, Lepage C, Faivre J, et al. Why do results conflict regarding the prognostic value of the methylation status in colon cancers? The role of the preservation method. BMC Cancer. 2012;12:12.CrossRefGoogle Scholar
  14. 14.
    Fabris S, Bollati V, Agnelli L, Morabito F, Motta V, Cutrona G, et al. Biological and clinical relevance of quantitative global methylation of repetitive DNA sequences in chronic lymphocytic leukemia. Epigenetics. 2011;6(2):188–94.CrossRefGoogle Scholar
  15. 15.
    Aoki Y, Nojima M, Suzuki H, Yasui H, Maruyama R, Yamamoto E, et al. Genomic vulnerability to LINE-1 hypomethylation is a potential determinant of the clinicogenetic features of multiple myeloma. Genome Med. 2012;4(12):101.CrossRefGoogle Scholar
  16. 16.
    Ting DT, Lipson D, Paul S, Brannigan BW, Akhavanfard S, Coffman EJ, et al. Aberrant overexpression of satellite repeats in pancreatic and other epithelial cancers. Science. 2011;331(6017):593–6.CrossRefGoogle Scholar
  17. 17.
    Rosic S, Kohler F, Erhardt S. Repetitive centromeric satellite RNA is essential for kinetochore formation and cell division. J Cell Biol. 2014;207(3):335–49.CrossRefGoogle Scholar
  18. 18.
    Zhu Q, Pao GM, Huynh AM, Suh H, Tonnu N, Nederlof PM, et al. BRCA1 tumour suppression occurs via heterochromatin-mediated silencing. Nature. 2011;477(7363):179–84.CrossRefGoogle Scholar
  19. 19.
    Jeong S, Lee K, Wen X, Kim Y, Cho NY, Jang JJ, et al. Tumoral LINE-1 hypomethylation is associated with poor survival of patients with intrahepatic cholangiocarcinoma. BMC Cancer. 2017;17(1):588.CrossRefGoogle Scholar
  20. 20.
    Min J, Choi B, Han TS, Lee HJ, Kong SH, Suh YS, et al. Methylation levels of LINE-1 as a useful marker for venous invasion in both FFPE and frozen tumor tissues of gastric cancer. Mol Cells. 2017;40(5):346–54.Google Scholar
  21. 21.
    Batsakis JG. Nerves and neurotropic carcinomas. Ann Otol Rhinol Laryngol. 1985;94(4 Pt 1):426–7.Google Scholar
  22. 22.
    Amit M, Na’ara S, Gil Z. Mechanisms of cancer dissemination along nerves. Nat Rev Cancer. 2016;16(6):399–408.CrossRefGoogle Scholar
  23. 23.
    Rodriguez J, Frigola J, Vendrell E, Risques RA, Fraga MF, Morales C, et al. Chromosomal instability correlates with genome-wide DNA demethylation in human primary colorectal cancers. Cancer Res. 2006;66(17):8462–9468.CrossRefGoogle Scholar
  24. 24.
    Suzuki K, Suzuki I, Leodolter A, Alonso S, Horiuchi S, Yamashita K, et al. Global DNA demethylation in gastrointestinal cancer is age dependent and precedes genomic damage. Cancer Cell. 2006;9(3):199–207.CrossRefGoogle Scholar
  25. 25.
    Cancer Genome Atlas Research N. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513(7517):202–9.CrossRefGoogle Scholar
  26. 26.
    Wylie A, Jones AE, D’Brot A, Lu WJ, Kurtz P, Moran JV, et al. p53 genes function to restrain mobile elements. Genes Dev. 2016;30(1):64–77.CrossRefGoogle Scholar
  27. 27.
    Saito M, Suzuki K, Maeda T, Kato T, Kamiyama H, Koizumi K, et al. The accumulation of DNA demethylation in Sat alpha in normal gastric tissues with Helicobacter pylori infection renders susceptibility to gastric cancer in some individuals. Oncol Rep. 2012;27(6):1717–25.Google Scholar
  28. 28.
    Liu J, Lichtenberg T, Hoadley KA, Poisson LM, Lazar AJ, Cherniack AD, et al. An integrated TCGA pan-cancer clinical data resource to drive high-quality survival outcome analytics. Cell. 2018;173(2):400–16.CrossRefGoogle Scholar

Copyright information

© The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2018

Authors and Affiliations

  • Younghoon Kim
    • 1
    • 2
  • Xianyu Wen
    • 1
    • 2
  • Seorin Jeong
    • 2
  • Nam-Yun Cho
    • 2
  • Woo Ho Kim
    • 1
  • Gyeong Hoon Kang
    • 1
    • 2
    Email author
  1. 1.Department of PathologySeoul National University College of MedicineSeoulSouth Korea
  2. 2.Laboratory of Epigenetics, Cancer Research InstituteSeoul National University College of MedicineSeoulSouth Korea

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