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The Combined Expression of Metaplasia Biomarkers Predicts the Prognosis Of Gastric Cancer

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

Abstract

Background

Our previous study indicated that gene expression profiling of intestinal metaplasia (IM) or spasmolytic polypeptide-expressing metaplasia (SPEM) can identify useful prognostic markers of early-stage gastric cancer, and seven metaplasia biomarkers (MUC13, CDH17, OLFM4, KRT20, LGALS4, MUC5AC, and REG4) were selectively expressed in 17–50% of gastric cancer tissues. We investigated whether the combined expression of these metaplasia biomarkers could predict the prognosis of advanced stage gastric cancer.

Methods

The expression of seven metaplasia biomarkers was evaluated immunohistochemically using tissue microarrays comprised of 450 gastric cancer patients. The clinicopathologic correlations and the prognostic impact were analyzed according to the expression of multiple biomarkers.

Results

MUC13, CDH17, LGALS4, and REG4 were significant prognostic biomarkers in univariate analysis. No expression of four markers was found in 56 cases (14.2%); 1 marker was seen in 67 cases (17%), 2 in 106 cases (27%), 3 in 101 cases (25.7%), and 4 in 63 cases (16%). Patients in which two or fewer proteins were expressed (group B) showed younger age, undifferentiated or diffuse type cancer, larger tumor size, larger number of metastatic lymph nodes, and more advanced stage than those in which three or more proteins were expressed (group A). In undifferentiated or stage II/III gastric cancer, the prognosis of group B was significantly poorer than that of group A by multivariate analysis.

Conclusions

The combined loss of expression of multiple metaplasia biomarkers is considered an independent prognostic indicator in undifferentiated or stage II/III gastric cancer.

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References

  1. Van De Vijver MJ, He YD, van’t Veer LJ, Dai H, Hart AA, Voskuil DW, Schreiber GJ, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347:1999–2009.

    Article  PubMed  Google Scholar 

  2. Beer DG, Kardia SLR, Huang CC, Giordano TJ, Levin AM, Misek DE, Lin L, et al. Gene-expression profiles predict survival of patients with lung adenocarcinoma. Nat Med. 2002;8:816–24.

    PubMed  CAS  Google Scholar 

  3. Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI, Gascoyne RD, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:1937–47.

    Article  PubMed  Google Scholar 

  4. Wang Y, Jatkoe T, Zhang Y, Mutch MG, Talantov D, Jiang J, McLeod HL, et al. Gene expression profiles and molecular markers to predict recurrence of Dukes’ B colon cancer. J Clin Oncol. 2004;22:1564–71.

    Article  PubMed  CAS  Google Scholar 

  5. DeRisi J, Penland L, Brown PO, Bittner ML, Meltzer PS, Ray M, Chen Y, et al. Use of a cDNA microarray to analyse gene expression patterns in human cancer. Nat Genet. 1996;14:457–60.

    Article  PubMed  CAS  Google Scholar 

  6. Bubendorf L, Nocito A, Moch H, Sauter G. Tissue microarray (TMA) technology: miniaturized pathology archives for high-throughput in situ studies. J Pathol. 2001;195:72–9.

    Article  PubMed  CAS  Google Scholar 

  7. Lee HS, Cho SB, Lee HE, Kim MA, Kim JH, Park DJ, Yang HK, et al. Protein expression profiling and molecular classification of gastric cancer by the tissue array method. Clin Cancer Res. 2007;13:4154–63.

    Article  PubMed  CAS  Google Scholar 

  8. Yasui W, Oue N, Ito R, Kuraoka K, Nakayama H. Search for new biomarkers of gastric cancer through serial analysis of gene expression and its clinical implications. Cancer Sci. 2004;95:385–92.

    Article  PubMed  CAS  Google Scholar 

  9. Oue N, Sentani K, Noguchi T, Ohara S, Sakamoto N, Hayashi T, Anami K, et al. Serum olfactomedin 4 (GW112, hGC-1) in combination with Reg IV is a highly sensitive biomarker for gastric cancer patients. Int J Cancer. 2009;125:2383–92.

    Article  PubMed  CAS  Google Scholar 

  10. Nam KT, Lee HJ, Mok H, Romero-Gallo J, Crowe Jr JE, Peek Jr RM, Goldenring JR. Amphiregulin-deficient mice develop spasmolytic polypeptide expressing metaplasia and intestinal metaplasia. Gastroenterology. 2009;136:1288–96.

    Article  PubMed  CAS  Google Scholar 

  11. Lee HJ, Nam KT, Park HS, Kim MA, LaFleur BJ, Aburatani H, Yang HK, et al. Gene expression profiling of metaplastic lineages identifies CDH17 as a prognostic marker in early stage gastric cancer. Gastroenterology. 2010;139:213–25.

    Article  PubMed  CAS  Google Scholar 

  12. Nozaki K, Ogawa M, Williams JA, Lafleur BJ, Ng V, Drapkin RI, Mills JC, et al. A molecular signature of gastric metaplasia arising in response to acute parietal cell loss. Gastroenterology 2008;134:511–22.

    Article  PubMed  CAS  Google Scholar 

  13. Zheng H, Xu X, Miao YU, Takahashi H, Masuda S, Takano Y. The role of Reg IV gene and its encoding product in gastric carcinogenesis. Hum Pathol. 2010;41:59–69.

    Article  PubMed  CAS  Google Scholar 

  14. Nakamura T, Yao T, Kabashima A, Nishiyama K, Maehara Y, Tsuneyoshi M. Loss of phenotypic expression is related to tumour progression in early gastric differentiated adenocarcinoma. Histopathology. 2005;47:357–67.

    Article  PubMed  CAS  Google Scholar 

  15. Kuniyasu H, Oue N, Sasahira T, Yi L, Moriwaka Y, Shimomoto T, Fujii K, et al. Reg IV enhances peritoneal metastasis in gastric carcinomas. Cell Prolif. 2009;42:110–21.

    Article  PubMed  CAS  Google Scholar 

  16. Tahara E. Molecular mechanism of stomach carcinogenesis. J Cancer Res Clin Oncol. 1993;119:265–72.

    Article  PubMed  CAS  Google Scholar 

  17. Hippo Y, Yashiro M, Ishii M, Taniguchi H, Tsutsumi S, Hirakawa K, Kodama T, et al. Differential gene expression profiles of scirrhous gastric cancer cells with high metastatic potential to peritoneum or lymph nodes. Cancer Res. 2001;61:889–95.

    PubMed  CAS  Google Scholar 

  18. Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma, 2nd English edn. Gastric Cancer. 1998;1:10–24.

    Article  PubMed  Google Scholar 

  19. Edge SB, Byrd DR, Compton CC. AJCC cancer staging manual, 7th edn. New York: Springer; 2009.

    Google Scholar 

  20. Yamamoto E, Suzuki H, Takamaru H, Yamamoto H, Toyota M, Shinomura Y. Role of DNA methylation in the development of diffuse-type gastric cancer. Digestion. 2011;83:241–9.

    Article  PubMed  CAS  Google Scholar 

  21. Tamura G, Sato K, Akiyama S, Tsuchiya T, Endoh Y, Usuba O, Kimura W, et al. Molecular characterization of undifferentiated-type gastric carcinoma. Lab Investig. 2001;81:593–8.

    Article  PubMed  CAS  Google Scholar 

  22. Saito A, Shimoda T, Nakanishi Y, Ochiai A, Toda G. Histologic heterogeneity and mucin phenotypic expression in early gastric cancer. Pathol Int. 2001;51:165–71.

    Article  PubMed  CAS  Google Scholar 

  23. Ikeda Y, Mori M, Kamakura T, Haraguchi Y, Saku M, Sugimachi K. Increased incidence of undifferentiated type of gastric cancer with tumor progression in 912 patients with early gastric cancer and 1245 with advanced gastric cancer. Cancer. 1994;73:2459–63.

    Article  PubMed  CAS  Google Scholar 

  24. Gessner R, Tauber R. Intestinal cell adhesion molecules: liver intestine cadherin. Ann N Y Acad Sci. 2000;915:136–43.

    Article  PubMed  CAS  Google Scholar 

  25. Williams SJ, Wreschner DH, Tran M, Eyre HJ, Sutherland GR, McGuckin MA. Muc13, a novel human cell surface mucin expressed by epithelial and hemopoietic cells. J Biol Chem. 2001;276:18327–36.

    Article  PubMed  CAS  Google Scholar 

  26. Shimamura T, Ito H, Shibahara J, Watanabe A, Hippo Y, Taniguchi H, Chen Y, et al. Overexpression of MUC13 is associated with intestinal-type gastric cancer. Cancer Sci. 2005;96:265–73.

    Article  PubMed  CAS  Google Scholar 

  27. Demetter P, Nagy N, Martin B, Mathieu A, Dumont P, Decaestecker C, Salmon I. The galectin family and digestive disease. J Pathol. 2008;215:1–12.

    Article  PubMed  CAS  Google Scholar 

  28. Huflejt ME, Leffler H. Galectin-4 in normal tissues and cancer. Glycoconj J. 2004;20:247–55.

    Article  PubMed  CAS  Google Scholar 

  29. Balan V, Nangia-Makker P, Raz A. Galectins as cancer biomarkers. Cancers. 2010;2:592–610.

    Article  CAS  Google Scholar 

  30. Terazono K, Yamamoto H, Takasawa S, Shiga K, Yonemura Y, Tochino Y, Okamoto H. A novel gene activated in regenerating islets. J Biol Chem. 1988;263:2111–4.

    PubMed  CAS  Google Scholar 

  31. Yamagishi H, Fukui H, Sekikawa A, Kono T, Fujii S, Ichikawa K, Tomita S, et al. Expression profile of REG family proteins REG Iα and REG IV in advanced gastric cancer: comparison with mucin phenotype and prognostic markers. Mod Pathol. 2009;22:906–13.

    Article  PubMed  CAS  Google Scholar 

  32. Oue N, Mitani Y, Aung PP, Sakakura C, Takeshima Y, Kaneko M, Noguchi T, et al. Expression and localization of Reg IV in human neoplastic and non-neoplastic tissues: Reg IV expression is associated with intestinal and neuroendocrine differentiation in gastric adenocarcinoma. J Pathol. 2005;207:185–98.

    Article  PubMed  CAS  Google Scholar 

  33. Mitani Y, Oue N, Matsumura S, Yoshida K, Noguchi T, Ito M, Tanaka S, et al. Reg IV is a serum biomarker for gastric cancer patients and predicts response to 5-fluorouracil-based chemotherapy. Oncogene. 2007;26:4383–93.

    Article  PubMed  CAS  Google Scholar 

  34. Eidelman S, Damsky CH, Wheelock MJ, Damjanov I. Expression of the cell–cell adhesion glycoprotein cell-CAM 120/80 in normal human tissues and tumors. Am J Pathol. 1989;135:101–10.

    PubMed  CAS  Google Scholar 

  35. Hirohashi S. Inactivation of the E-cadherin-mediated cell adhesion system in human cancers. Am J Pathol. 1998;1:333–9.

    Article  Google Scholar 

  36. Mayer B, Johnson JP, Leitl F, Jauch KW, Heiss MM, Schildberg FW, Birchmeier W, et al. E-cadherin expression in primary and metastatic gastric cancer: down-regulation correlates with cellular dedifferentiation and glandular disintegration. Cancer Res. 1993;53:1690–5.

    PubMed  CAS  Google Scholar 

  37. Mayer B, Jauch KW, Schildberg FW, Funke I, Gunthert U, Figdor CG, Johnson JP. De novo expression of CD44 and survival in gastric cancer. Lancet. 1993;342:1019–22.

    Article  PubMed  CAS  Google Scholar 

  38. Brackenbury R. Molecular mechanisms of cell adhesion in normal and transformed cells. Cancer Metastasis Rev. 1985;4:41–58.

    Article  PubMed  CAS  Google Scholar 

  39. Shimada Y, Yamasaki S, Hashimoto Y, Ito T, Kawamura J, Soma T, Ino Y, et al. Clinical significance of dysadherin expression in gastric cancer patients. Clin Cancer Res. 2004;10:2818–23.

    Article  PubMed  CAS  Google Scholar 

  40. Park JH, Lee BL, Yoon J, Kim J, Kim MA, Yang HK, Kim WH. Focal adhesion kinase (FAK) gene amplification and its clinical implications in gastric cancer. Hum Pathol. 2010;41:1664–73.

    Article  PubMed  CAS  Google Scholar 

  41. Wiksten JP, Lundin J, Nordling S, Lundin M, Kokkola A, von Boguslawski K, Haglund C. Epithelial and stromal syndecan 1 expression as predictor of outcome in patients with gastric cancer. Int J Cancer. 2001;95:1–6.

    Article  PubMed  CAS  Google Scholar 

  42. Lee HS, Lee HK, Kim HS, Yang HK, Kim YI, Kim WH. MUC1, MUC2, MUC5AC, and MUC6 expressions in gastric carcinomas. Cancer. 2001;92:1427–34.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

This study was supported by funding to HJL from the SNUH Research Fund (grant number 05-2009-002) and funding to JRG from NIH RO1 DK071590, RO1 DK071590-S1, and a VA Merit Review Award.

Conflict of interest

The authors declare no conflict of interest.

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Correspondence to Hyuk-Joon Lee MD, PhD.

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Suh, YS., Lee, HJ., Jung, EJ. et al. The Combined Expression of Metaplasia Biomarkers Predicts the Prognosis Of Gastric Cancer. Ann Surg Oncol 19, 1240–1249 (2012). https://doi.org/10.1245/s10434-011-2125-1

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  • DOI: https://doi.org/10.1245/s10434-011-2125-1

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