Skip to main content
SpringerLink
Log in

Promoter hypermethylation of p16 gene in pre- and post-operative plasma of patients with gastric adenocarcinoma

  • Articles
  • Published:
Chinese Journal of Cancer Research

Abstracts

Objective: To detect promoter hypermethylation of p16 gene in matched pre- and post-operative plasma of patients with gastric adenocarcinoma for evaluating the effectiveness of therapeutic intervention. Methods: Tissue samples, pre- and post-operative plasma of 84 patients were collected. Plasma of 15 healthy people was collected as control. After sodium-bisulfite treatment, extracted DNA was amplified for p16 promoter by methylation-specific polymerase chain reaction (MSP). The PCR products were detected by both gel-ethidium bromide electrophoresis and high performance liquid chromatogram (HPLC). Results: Among 84 patients, p16 hypermethylation was detected in 26 (31.0%) cancer tissues and 2 (0.02%) tumor-adjacent tissues and 12 (14.3%) pre-operative plasma, while negative in plasma of healthy people. For positive plasma cases, the paired tumor tissues were confirmed to be methylated. Within available 30 pairs of matched pre- and post-operative plasma, 6 pre-operative plasma was positive, and only 1 of 6 plasma remained hypermethylated after surgery. The results detected by HPLC exactly matched those by gel-electrophoresis. Conclusion: The alteration of status of p16 hypermethylation in post-operative plasma is considered the consequences of surgical intervention. Although p16 hypermethylation has no role in pre-operative staging of gastric cancer, detecting hypermethylated p16 in plasma could be utilized in monitoring patients after surgery.

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

References

  1. Terry MB, Gaudet MM, Gammon MD. The epidemiology of gastric cancer [J]. Semin Radiat Oncol 2002; 12:111–27.

    Article  PubMed  Google Scholar 

  2. Roder DM. The epidemiology of gastric cancer [J]. Gastric Cancer 2002; 5(Suppl 1):5–11.

    Article  PubMed  Google Scholar 

  3. Maehara Y, Kakeji Y, Oda S, et al. Time trends of surgical treatment and the prognosis for Japanese patients with gastric cancer [J]. Br J Cancer 2000; 83:986–91.

    Article  PubMed  CAS  Google Scholar 

  4. Hohenberger P, Gretschel S. Gastric cancer [J]. Lancet 2003; 362:305–15.

    Article  PubMed  Google Scholar 

  5. Roth AD. Curative treatment of gastric cancer: towards a multidisciplinary approach? [J]. Crit Rev Oncol Hematol 2003; 46:59–100.

    Article  PubMed  Google Scholar 

  6. Jen J, Wu L, Sidransky D. An overview on the isolation and analysis of circulating tumor DNA in plasma and serum [J]. Ann N Y Acad Sci 2000; 906:8–12.

    Article  PubMed  CAS  Google Scholar 

  7. Johnson PJ, Lo YM. Plasma nucleic acids in the diagnosis and management of malignant disease [J]. Clin Chem 2002; 48:1186–93.

    PubMed  CAS  Google Scholar 

  8. Anker P, Mulcahy H, Stroun M. Circulating nucleic acids in plasma and serum as a noninvasive investigation for cancer: time for large-scale clinical studies? [J]. Int J Cancer 2003; 103:149–52.

    Article  PubMed  CAS  Google Scholar 

  9. Burchill SA, Selby PJ. Molecular detection of low-level disease in patients with cancer [J]. J Pathol 2000; 190:6–14.

    Article  PubMed  CAS  Google Scholar 

  10. Chan KC, Lo YM. Circulating nucleic acids as a tumor marker [J]. Histol Histopathol 2002; 17:937–43.

    PubMed  CAS  Google Scholar 

  11. Esteller M. Relevance of DNA methylation in the management of cancer [J]. Lancet Oncol 2003; 4:351–8.

    Article  PubMed  CAS  Google Scholar 

  12. Patel A, Groopman JD, Umar A. DNA methylation as a cancer-specific biomarker: from molecules to populations [J]. Ann N Y Acad Sci 2003; 983:286–97.

    Article  PubMed  CAS  Google Scholar 

  13. Anker P, Stroun M. Circulating DNA in plasma or serum [J]. Medicine (B Aires) 2000; 60:699–702.

    CAS  Google Scholar 

  14. Lee TL, Leung WK, Chan MW, et al. Detection of gene promoter hypermethylation in the tumor and serum of patients with gastric carcinoma [J]. Clin Cancer Res 2002; 8:1761–6.

    PubMed  CAS  Google Scholar 

  15. Yu J, Leung WK, Lee TL, et al. Promoter hypermethylation of cyclooxygenase-2 in gastric carcinoma [J]. Int J Oncol 2003; 22:1025–31.

    PubMed  CAS  Google Scholar 

  16. Iida S, Akiyama Y, Nakajima T, et al. Alterations and hypermethylation of the p14 ARF) gene in gastric cancer [J]. Int J Cancer 2000; 87:654–8.

    Article  PubMed  CAS  Google Scholar 

  17. Kanyama Y, Hibi K, Nakayama H, et al. Detection of p16 promoter hypermethylation in serum of gastric cancer patients [J]. Cancer Sci 2003; 94:418–20.

    Article  PubMed  CAS  Google Scholar 

  18. Herman JG, Graff JR, Myohanen S, et al. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands [J]. Proc Natl Acad Sci USA 1996; 93:9821–6.

    Article  PubMed  CAS  Google Scholar 

  19. Kamb A, Gruis NA, Weaver-Feldhaus J, et al. A cell cycle regulator potentially involved in genesis of many tumor types [J]. Science 1994; 264:436–40.

    Article  PubMed  CAS  Google Scholar 

  20. Esteller M, Fraga MF, Paz MF, et al. Cancer epigenetics and methylation [J]. Science 2002; 297:1807–8.

    Article  PubMed  Google Scholar 

  21. Herman JG, Merlo A, Mao L, et al. Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers [J]. Cancer Res 1995; 55:4525–30.

    PubMed  CAS  Google Scholar 

  22. Merlo A, Herman JG, Mao L, et al. 5′ CpG island methylation is associated with transcriptional silencing of the tumor suppressor p16/CDKN2/MTS1 in human cancers [J]. Nat Med 1995; 1:686–92.

    Article  PubMed  CAS  Google Scholar 

  23. Gonzalez-Zulueta M, Bender CM, Yang AS, et al. Methylation of the 5′ CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissues correlates with gene silencing [J]. Cancer Res 1995; 55:4531–5.

    PubMed  CAS  Google Scholar 

  24. Sakata K, Tamura G, Maesawa C, et al. Loss of heterozygosity on the short arm of chromosome 9 without p16 gene mutation in gastric carcinomas [J]. Jpn J Cancer Res 1995; 86:333–5.

    PubMed  CAS  Google Scholar 

  25. Jang TJ, Kim DI, Shin YM, et al. p16(INK4a) Promoter hypermethylation of non-tumorous tissue adjacent to gastric cancer is correlated with glandular atrophy and chronic inflammation [J]. Int J Cancer 2001; 93:629–34.

    Article  PubMed  CAS  Google Scholar 

  26. Ficorella C, Cannita K, Ricevuto E, et al. P16 hypermethylation contributes to the characterization of gene inactivation profiles in primary gastric cancer [J]. Oncol Rep 2003; 10:169–73.

    PubMed  CAS  Google Scholar 

  27. Oue N, Motoshita J, Yokozaki H, et al. Distinct promoter hypermethylation of p16INK4a, CDH1, and RAR-beta in intestinal, diffuse-adherent, and diffuse-scattered type gastric carcinomas [J]. J Pathol 2002; 198:55–9.

    Article  PubMed  CAS  Google Scholar 

  28. Tsujimoto H, Hagiwara A, Sugihara H, et al. Promoter methylations of p16INK4a and p14ARF genes in early and advanced gastric cancer. Correlations of the modes of their occurrence with histologic type [J]. Pathol Res Pract 2002; 198:785–94.

    Article  PubMed  CAS  Google Scholar 

  29. Tang S, Luo H, Yu J, et al. Relationship between alterations of p16(INK4a) and p14(ARF) genes of CDKN2A locus and gastric carcinogenesis [J]. Chin Med J (Engl) 2003; 116:1083–7.

    CAS  Google Scholar 

  30. Lee JH, Park SJ, Abraham SC, et al. Frequent CpG island methylation in precursor lesions and early gastric adenocarcinomas [J]. Oncogene 2004.

  31. Jahr S, Hentze H, Englisch S, et al. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells [J]. Cancer Res 2001; 61:1659–65.

    PubMed  CAS  Google Scholar 

  32. Wang BG, Huang HY, Chen YC, et al. Increased plasma DNA integrity in cancer patients [J]. Cancer Res 2003; 63:3966–8.

    PubMed  CAS  Google Scholar 

  33. Lo YM, Leung SF, Chan LY, et al. Kinetics of plasma Epstein-Barr virus DNA during radiation therapy for nasopharyngeal carcinoma [J]. Cancer Res 2000; 60:2351–5.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgical Oncology, Peking University School of Oncology, Beijing Institute for Cancer Research, Beijing Cancer Hospital, 100036, Beijing

    Liu Ya-hang, Li Zi-yu, Zhang Lian-hai, Ren Hui, Zhang Gui-guo & Ji Jia-fu

  2. Department of Biochemistry, Peking University School of Oncology, Beijing Institute for Cancer Research, Beijing Cancer Hospital, 100036, Beijing

    Deng Guo-ren

  3. Department of Anesthesiology, the Affiliated Hospital of Inner Mongolia Medical College, 010050, Huhehaote

    Qin Fei

  4. Department of Surgery, the Affiliated Hospital of Inner Mongolia Medical College, 010050, Huhehaote

    Kong Guang-zhong

Authors
  1. Liu Ya-hang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Li Zi-yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhang Lian-hai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ren Hui
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhang Gui-guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qin Fei
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kong Guang-zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Deng Guo-ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ji Jia-fu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ji Jia-fu.

Additional information

Foundation item: This work was supported in part by Science Research Foundation of Peking University School of Oncology (00-01 and 04-01).

These two authors contributed equally to this work.

Biography: LIU Ya-hang (1972–), female, master of medicine, Peking University, attending surgeon of the Affiliated Hospital of Inner Mongolia Medical College, majors in surgical oncology; Li Zi-yu (1971–), male, postdoctoral fellow of Peking University, attending surgeon of Beijing Cancer Hospital, majors in surgical oncology.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, Yh., Li, Zy., Zhang, Lh. et al. Promoter hypermethylation of p16 gene in pre- and post-operative plasma of patients with gastric adenocarcinoma. Chin. J. Cancer Res. 17, 28–34 (2005). https://doi.org/10.1007/s11670-005-0006-5

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11670-005-0006-5

Key words

CLC number

Search

Navigation