Skip to main content

Advertisement

Log in

Circulating cell-free human telomerase reverse transcriptase mRNA in plasma and its potential diagnostic and prognostic value for gastric cancer

  • Original Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

Our aims were to detect circulating cell-free human telomerase reverse transcriptase (hTERT) mRNA in the plasma of gastric cancer patients and evaluate its potential diagnostic and prognostic value.

Methods

Real-time quantitative reverse transcription-polymerase chain reaction was employed to detect circulating cell-free hTERT mRNA from 118 gastric cancer patients, 40 chronic atrophic gastritis (CAG) patients, and 58 healthy controls.

Results

Circulating cell-free hTERT mRNA was detected in all gastric cancer patients, 39 (97.5 %) CAG patients and 56 (96.6 %) healthy control individuals, respectively. However, it was higher in gastric cancer than in CAG and healthy controls (all at P < 0.05). Moreover, its high level was significantly correlated with clinical stages (P < 0.001) and lymph nodes metastasis (P < 0.001). There was no difference between circulating cell-free mRNA and other parameters. The area under the receiver operating characteristic (ROC) curve was 0.891, and the optimal cut-off point was 0.18, providing a sensitivity of 66 % and a specificity of 87 %. The ROC analysis showed that the diagnosis capability of circulating cell-free mRNA was statistically significantly higher than that of carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA19-9), alone [CEA (0.656); CA19-9 (0.722)] or in combination (0.756). Kaplan–Meier analysis demonstrated a correlation between increased circulating cell-free hTERT mRNA and reduced disease-free survival (P < 0.001) and overall survival (P < 0.001). Cox analysis indicated that it was an independent prognostic factor for disease-free survival and overall survival.

Conclusions

We concluded that circulating cell-free hTERT mRNA might serve as a potential and useful noninvasive tumor marker for gastric cancer.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

GC:

Gastric cancer

CEA:

Carcinoembryonic antigen

CA19-9:

Cancer antigen 19-9

CAG:

Chronic atrophic gastritis

AUC:

The area under the ROC curve

ROC:

Receiver operating characteristic

DFS:

Disease-free survival

OS:

Overall survival

hTERT:

Human telomerase reverse transcriptase

C q :

Quantification cycle

RT-qPCR:

Reverse transcription quantitative real-time PCR

References

  1. Jemal A, Bray F, Center MM et al (2011) Global cancer statistics. CA Cancer J Clin 61:69–90

    Article  PubMed  Google Scholar 

  2. Menges M (2011) Gastric cancer: Where is the place for the surgeon, the oncologist and the endoscopist today? World J Gastrointest Oncol 3:10–13

    Article  PubMed  Google Scholar 

  3. Dilege E, Mihmanli M, Demir U et al (2010) Prognostic value of preoperative CEA and CA19-9 levels in resectable gastric cancer. Hepatogastroenterology 57:674–677

    PubMed  Google Scholar 

  4. Schneider J, Schulze G (2003) Comparison of tumor M2-pyruvate kinase (tumor M2-PK), carcinoembryonic antigen (CEA), carbohydrate antigens CA 19-9 and CA 72-4 in the diagnosis of gastrointestinal cancer. Anticancer Res 23:5089–5093

    PubMed  CAS  Google Scholar 

  5. Kopreski MS, Benko FA, Kwak LW et al (1999) Detection of tumor messenger RNA in the serum of patients with malignant melanoma. Clin Cancer Res 5:1961–1965

    PubMed  CAS  Google Scholar 

  6. Schwarzenbach H, Hoon DS, Pantel K (2011) Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer 11:426–437

    Article  PubMed  CAS  Google Scholar 

  7. Dasi F, Martinez-Rodes P, March JA et al (2006) Real-time quantification of human telomerase reverse transcriptase mRNA in the plasma of patients with prostate cancer. Ann N Y Acad Sci 1075:204–210

    Article  PubMed  CAS  Google Scholar 

  8. Kudo Y, Ochi T, Shimada H et al (2008) Utility of plasma circulating mRNA as a marker to detect hepatic injury. J Vet Med Sci 70:993–995

    Article  PubMed  Google Scholar 

  9. Takahashi S, Miura N, Harada T et al (2010) Prognostic impact of clinical course-specific mRNA expression profiles in the serum of perioperative patients with esophageal cancer in the ICU: a case control study. J Transl Med 8:103

    Article  PubMed  Google Scholar 

  10. Garcia V, Garcia JM, Pena C et al (2008) Free circulating mRNA in plasma from breast cancer patients and clinical outcome. Cancer Lett 263:312–320

    Article  PubMed  CAS  Google Scholar 

  11. Garcia V, Garcia JM, Silva J et al (2009) Extracellular tumor-related mRNA in plasma of lymphoma patients and survival implications. PLoS ONE 4:e8173

    Article  PubMed  Google Scholar 

  12. Nakamura TM, Morin GB, Chapman KB et al (1997) Telomerase catalytic subunit homologs from fission yeast and human. Science 277:955–959

    Article  PubMed  CAS  Google Scholar 

  13. Yuan J, Yang BM, Zhong ZH et al (2009) Upregulation of survivin during immortalization of nontransformed human fibroblasts transduced with telomerase reverse transcriptase. Oncogene 28:2678–2689

    Article  PubMed  CAS  Google Scholar 

  14. Xu Y, Yu M, Wu F et al (2009) Effects of ectopic expression of human telomerase reverse transcriptase on immortalization of feather keratinocyte stem cells. J Exp Zool B Mol Dev Evol 312:872–884

    Article  PubMed  Google Scholar 

  15. Yip YL, Tsang CM, Deng W et al (2010) Expression of Epstein–Barr virus-encoded LMP1 and hTERT extends the life span and immortalizes primary cultures of nasopharyngeal epithelial cells. J Med Virol 82:1711–1723

    Article  PubMed  CAS  Google Scholar 

  16. Mai W, Kawakami K, Shakoori A et al (2009) Deregulated GSK3{beta} sustains gastrointestinal cancer cells survival by modulating human telomerase reverse transcriptase and telomerase. Clin Cancer Res 15:6810–6819

    Article  PubMed  CAS  Google Scholar 

  17. Suzuki K, Kashimura H, Ohkawa J et al (2000) Expression of human telomerase catalytic subunit gene in cancerous and precancerous gastric conditions. J Gastroenterol Hepatol 15:744–751

    Article  PubMed  CAS  Google Scholar 

  18. Yoo J, Park SY, Kang SJ et al (2003) Expression of telomerase activity, human telomerase RNA, and telomerase reverse transcriptase in gastric adenocarcinomas. Mod Pathol 16:700–707

    Article  PubMed  Google Scholar 

  19. Wang W, Luo HS, Yu BP (2004) Expression of NF-kappaB and human telomerase reverse transcriptase in gastric cancer and precancerous lesions. World J Gastroenterol 10:177–181

    PubMed  CAS  Google Scholar 

  20. Gigek CO, Leal MF, Silva PN et al (2009) hTERT methylation and expression in gastric cancer. Biomarkers 14:630–636

    Article  PubMed  CAS  Google Scholar 

  21. Chen XQ, Bonnefoi H, Pelte MF et al (2000) Telomerase RNA as a detection marker in the serum of breast cancer patients. Clin Cancer Res 6:3823–3826

    PubMed  CAS  Google Scholar 

  22. Miura N, Nakamura H, Sato R et al (2006) Clinical usefulness of serum telomerase reverse transcriptase (hTERT) mRNA and epidermal growth factor receptor (EGFR) mRNA as a novel tumor marker for lung cancer. Cancer Sci 97:1366–1373

    Article  PubMed  CAS  Google Scholar 

  23. Tani N, Ichikawa D, Ikoma D et al (2007) Circulating cell-free mRNA in plasma as a tumor marker for patients with primary and recurrent gastric cancer. Anticancer Res 27:1207–1212

    PubMed  CAS  Google Scholar 

  24. Miura N, Shiota G, Nakagawa T et al (2003) Sensitive detection of human telomerase reverse transcriptase mRNA in the serum of patients with hepatocellular carcinoma. Oncology 64:430–434

    Article  PubMed  CAS  Google Scholar 

  25. Khan FA, Shukla AN (2006) Pathogenesis and treatment of gastric carcinoma: “an up-date with brief review”. J Cancer Res Ther 2:196–199

    Article  PubMed  CAS  Google Scholar 

  26. Yang SM, Fang DC, Yang JL et al (2008) Antisense human telomerase reverse transcriptase could partially reverse malignant phenotypes of gastric carcinoma cell line in vitro. Eur J Cancer Prev 17:209–217

    Article  PubMed  CAS  Google Scholar 

  27. Ebert MP, Rocken C (2006) Molecular screening of gastric cancer by proteome analysis. Eur J Gastroenterol Hepatol 18:847–853

    Article  PubMed  CAS  Google Scholar 

  28. Oh BK, Kim H, Park YN et al (2008) High telomerase activity and long telomeres in advanced hepatocellular carcinomas with poor prognosis. Lab Invest 88:144–152

    Article  PubMed  CAS  Google Scholar 

  29. Taubert H, Wurl P, Greither T et al (2007) Stem cell-associated genes are extremely poor prognostic factors for soft-tissue sarcoma patients. Oncogene 26:7170–7174

    Article  PubMed  CAS  Google Scholar 

  30. Chen HH, Yu CH, Wang JT et al (2007) Expression of human telomerase reverse transcriptase (hTERT) protein is significantly associated with the progression, recurrence and prognosis of oral squamous cell carcinoma in Taiwan. Oral Oncol 43:122–129

    Article  PubMed  CAS  Google Scholar 

  31. Boldrini L, Pistolesi S, Gisfredi S et al (2006) Telomerase activity and hTERT mRNA expression in glial tumors. Int J Oncol 28:1555–1560

    PubMed  CAS  Google Scholar 

  32. Metzger R, Vallbohmer D, Muller-Tidow C et al (2009) Increased human telomerase reverse transcriptase (hTERT) mRNA expression but not telomerase activity is related to survival in curatively resected non-small cell lung cancer. Anticancer Res 29:1157–1162

    PubMed  CAS  Google Scholar 

  33. Grochola LF, Greither T, Taubert HW et al (2008) Prognostic relevance of hTERT mRNA expression in ductal adenocarcinoma of the pancreas. Neoplasia 10:973–976

    PubMed  CAS  Google Scholar 

  34. Kawai J, Kodera Y, Fujiwara M et al (2005) Telomerase activity as prognostic factor in gastrointestinal stromal tumors of the stomach. Hepatogastroenterology 52:959–964

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Authors thank Dr. Xiaoju Zhang (Department of Anesthesia, University of California, San Francisco) for critically reviewing the manuscript.

Conflict of interest

All the authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jia Shang.

About this article

Cite this article

Kang, Y., Zhang, J., Sun, P. et al. Circulating cell-free human telomerase reverse transcriptase mRNA in plasma and its potential diagnostic and prognostic value for gastric cancer. Int J Clin Oncol 18, 478–486 (2013). https://doi.org/10.1007/s10147-012-0405-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-012-0405-9

Keywords

Navigation