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The Global Histone Modification Pattern Correlates with Cancer Recurrence and Overall Survival in Gastric Adenocarcinoma

  • Gastrointestinal Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Epigenetic alterations such as DNA methylation and histone modification play important roles in carcinogenesis. It has been recently suggested that global histone modification patterns are independent predictors of cancer recurrence. In this study, we used immunohistochemistry to evaluate the patterns of histone H3 and H4 acetylation and trimethylation in gastric adenocarcinomas.

Methods

Double 2-mm core tissue microarrays were made from 261 paraffin-embedded gastric adenocarcinoma samples and examined by immunohistochemistry for histone H3 lysine 9 (H3K9) acetylation and trimethylation, histone H4 lysine 16 acetylation, and histone H4 lysine 20 trimethylation. Sections were graded according to the proportion of tumor cells showing nuclear staining.

Results

Trimethylation of H3K9 positively correlated with tumor stage (P = 0.043); lymphovascular invasion (P = 0.029), cancer recurrence (P = 0.043), and higher level of H3K9 trimethylation correlated with a poor survival rate (P = 0.008). Multivariate survival analysis showed that H3K9 trimethylation status is an independent prognostic factor (P = 0.014). After categorizing cases according to the dominant modification pattern, we found that methylation dominance was associated with lymphovascular invasion (P = 0.001), cancer recurrence (P = 0.001), and poor survival rate (P = 0.028). Methylation dominance was also an independent prognostic factor (P = 0.026) in multivariate survival analysis.

Conclusion

The pattern of histone modification as detected by immunohistochemistry may be useful as a predictor for the recurrence of cancer and may be an independent prognostic factor in gastric adenocarcinomas.

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References

  1. Akoh JA, Macintyre IM. Improving survival in gastric cancer: review of 5-year survival rates in English language publications from 1970. Br J Surg 1992; 79:293–9

    Article  PubMed  CAS  Google Scholar 

  2. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin 2006; 56:106–30

    PubMed  Google Scholar 

  3. Crew KD, Neugut AI. Epidemiology of gastric cancer. World J Gastroenterol 2006; 12:354–62

    PubMed  Google Scholar 

  4. Bae J-M, Won Y-J, Jung K-W, et al. Annual Report of the Central Cancer Registry in Korea-1999: Based on Registered Data from 128 Hospitals. Cancer Res Treat 2001; 33:367

    Google Scholar 

  5. Yasui W, Sentani K, Motoshita J, et al. Molecular pathobiology of gastric cancer. Scand J Surg 2006; 95:225–31

    PubMed  CAS  Google Scholar 

  6. Lee HS, Lee HK, Kim HS, et al. Tumour suppressor gene expression correlates with gastric cancer prognosis. J Pathol 2003; 200:39–46

    Article  PubMed  CAS  Google Scholar 

  7. Vogiatzi P, Vindigni C, Roviello F, et al. Deciphering the underlying genetic and epigenetic events leading to gastric carcinogenesis. J Cell Physiol 2007; 211:287–95

    Article  PubMed  CAS  Google Scholar 

  8. Sato F, Meltzer SJ. CpG island hypermethylation in progression of esophageal and gastric cancer. Cancer 2006; 106:483–93

    Article  PubMed  CAS  Google Scholar 

  9. Kurdistani SK. Histone modifications as markers of cancer prognosis: a cellular view. Br J Cancer 2007; 97:1–5

    Article  PubMed  CAS  Google Scholar 

  10. Kuo MH, Brownell JE, Sobel RE, et al. Transcription-linked acetylation by Gcn5p of histones H3 and H4 at specific lysines. Nature 1996; 383:269–72

    Article  PubMed  CAS  Google Scholar 

  11. Suka N, Suka Y, Carmen AA, et al. Highly specific antibodies determine histone acetylation site usage in yeast heterochromatin and euchromatin. Mol Cell 2001; 8:473–9

    Article  PubMed  CAS  Google Scholar 

  12. Peterson CL, Laniel MA. Histones and histone modifications. Curr Biol 2004; 14:R546–51

    Article  PubMed  CAS  Google Scholar 

  13. Rundlett SE, Carmen AA, Suka N, et al. Transcriptional repression by UME6 involves deacetylation of lysine 5 of histone H4 by RPD3. Nature 1998; 392:831–5

    Article  PubMed  CAS  Google Scholar 

  14. Vogelauer M, Wu J, Suka N, et al. Global histone acetylation and deacetylation in yeast. Nature 2000; 408:495–8

    Article  PubMed  CAS  Google Scholar 

  15. Kondo Y, Shen L, Issa JP. Critical role of histone methylation in tumor suppressor gene silencing in colorectal cancer. Mol Cell Biol 2003; 23:206–15

    Article  PubMed  CAS  Google Scholar 

  16. Watanabe Y, Toyota M, Kondo Y, et al. PRDM5 identified as a target of epigenetic silencing in colorectal and gastric cancer. Clin Cancer Res 2007; 13:4786–94

    Article  PubMed  CAS  Google Scholar 

  17. Mitani Y, Oue N, Hamai Y, et al. Histone H3 acetylation is associated with reduced p21(WAF1/CIP1) expression by gastric carcinoma. J Pathol 2005; 205:65–73

    Article  PubMed  CAS  Google Scholar 

  18. Ueno M, Toyota M, Akino K, et al. Aberrant methylation and histone deacetylation associated with silencing of SLC5A8 in gastric cancer. Tumour Biol 2004; 25:134–40

    Article  PubMed  CAS  Google Scholar 

  19. Kikuchi T, Itoh F, Toyota M, et al. Aberrant methylation and histone deacetylation of cyclooxygenase 2 in gastric cancer. Int J Cancer 2002; 97:272–7

    Article  PubMed  CAS  Google Scholar 

  20. Ono S, Oue N, Kuniyasu H, et al. Acetylated histone H4 is reduced in human gastric adenomas and carcinomas. J Exp Clin Cancer Res 2002; 21:377–82

    PubMed  CAS  Google Scholar 

  21. Takahashi H, Murai Y, Tsuneyama K, et al. Overexpression of phosphorylated histone H3 is an indicator of poor prognosis in gastric adenocarcinoma patients. Appl Immunohistochem Mol Morphol 2006; 14:296–302

    Article  PubMed  CAS  Google Scholar 

  22. Seligson DB, Horvath S, Shi T, et al. Global histone modification patterns predict risk of prostate cancer recurrence. Nature 2005; 435:1262–6

    Article  PubMed  CAS  Google Scholar 

  23. Marushige K. Activation of chromatin by acetylation of histone side chains. Proc Natl Acad Sci USA 1976; 73:3937–41

    Article  PubMed  CAS  Google Scholar 

  24. Vidali G, Ferrari N, Pfeffer U. Histone acetylation: a step in gene activation. Adv Exp Med Biol 1988; 231:583–96

    PubMed  CAS  Google Scholar 

  25. Profumo A, Querzola F, Vidali G. Core histone acetylation during lymphocyte activation. FEBS Lett 1989; 250:297–300

    Article  PubMed  CAS  Google Scholar 

  26. Heard E, Rougeulle C, Arnaud D, et al. Methylation of histone H3 at Lys-9 is an early mark on the X chromosome during X inactivation. Cell 2001; 107:727–38

    Article  PubMed  CAS  Google Scholar 

  27. Mermoud JE, Popova B, Peters AH, et al. Histone H3 lysine 9 methylation occurs rapidly at the onset of random X chromosome inactivation. Curr Biol 2002; 12:247–51

    Article  PubMed  CAS  Google Scholar 

  28. Nguyen CT, Weisenberger DJ, Velicescu M, et al. Histone H3-lysine 9 methylation is associated with aberrant gene silencing in cancer cells and is rapidly reversed by 5-aza-2’-deoxycytidine. Cancer Res 2002; 62:6456–61

    PubMed  CAS  Google Scholar 

  29. Schotta G, Lachner M, Sarma K, et al. A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin. Genes Dev 2004; 18:1251–62

    Article  PubMed  CAS  Google Scholar 

  30. Nakayama J, Rice JC, Strahl BD, et al. Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly. Science 2001; 292:110–3

    Article  PubMed  CAS  Google Scholar 

  31. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev 2002; 3:415–28

    CAS  Google Scholar 

  32. Hake SB, Xiao A, Allis CD. Linking the epigenetic ‘language’ of covalent histone modifications to cancer. Br J Cancer 2004; 90:761–9

    Article  PubMed  CAS  Google Scholar 

  33. Esteller M. Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev 2007; 8:286–98

    Article  CAS  Google Scholar 

  34. Wiencke JK, Zheng S, Morrison Z, et al. Differentially expressed genes are marked by histone 3 lysine 9 trimethylation in human cancer cells. Oncogene 2008; 27(17):2412–21

    Article  PubMed  CAS  Google Scholar 

  35. Fraga MF, Ballestar E, Villar-Garea A, et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Gen 2005; 37:391–400

    Article  CAS  Google Scholar 

  36. Wang Y, Fischle W, Cheung W, et al. Beyond the double helix: writing and reading the histone code. Novartis Found Symp 2004; 259:3–17; discussion 17–21, 163–9

    Article  PubMed  CAS  Google Scholar 

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Acknowledgement

The study was supported by KOSEF research grant R01-2004-000-10670-0

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Correspondence to Se Jin Jang MD.

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Park, Y.S., Jin, M.Y., Kim, Y.J. et al. The Global Histone Modification Pattern Correlates with Cancer Recurrence and Overall Survival in Gastric Adenocarcinoma. Ann Surg Oncol 15, 1968–1976 (2008). https://doi.org/10.1245/s10434-008-9927-9

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  • DOI: https://doi.org/10.1245/s10434-008-9927-9

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