Prognostic significance of HER2, p53, Ki67, MVD-CD34, Cox2, MMP7, and vimentin in gastric cancer
-
Amirhossein Razavirad
,
Ahad Mohammadnezhad
,
Saeed Soleymanjahi
,
Sanaz Rismanchi
,
Elnaz Saeedi
,
Amirafraz Fallah
,
Alireza Abdollahi
,
Saeid Amanpour
,
Kazem Zendehdel
Abstract
Background: Gastric cancer (GC) patients have a poor prognosis mainly due to late diagnosis. We aimed to study the prognostic effects of various biomarkers, including HER2, CD34, p53, Ki67, Cox2, MMP7, and vimentin in GC.Methods: We performed immunohistochemistry (IHC) to examine the expression of potential biomarkers in 140 GC patients. CD34 protein expression was quantified to assess angiogenesis through scoring microvessel density (MVD). We used a multivariable Cox-proportional hazard model to estimate hazard ratios (HRs) representing the prognostic role of the biomarkers and the clinicopathological parameters.Results: Patients diagnosed at the advanced tumor stage exhibited a significantly higher risk of mortality than those diagnosed at the early stages (HR = 5.96, CI: 3.73 – 9.51). We also observed higher risks of mortality in patients with high MVD-CD34 (HR = 5.35, CI: 2.36 – 12.12), HER2-positive (HR = 2.82, CI: 1.69 – 4.37), p53-positive (HR = 4.03, CI: 2.53 – 6.4), high Ki67 (HR = 4.34, CI: 2.64 – 7.13), high Cox2 (HR = 4.77, CI: 2.39 – 9.49), high MMP7 (HR = 2.75, CI: 1.53 – 4.94), and high vimentin (HR = 3.78, CI: 1.7 – 8.39) tumors compared to their corresponding reference groups. The association was statistically significant for HER2, p53, Ki67, Cox2, and MVD-CD34 among those diagnosed in an early stage.Conclusion: Overall, evaluation of tumor biomarkers in GC patients can result in more precise estimates of prognosis, especially in early-stage tumors. These biomarkers could potentially be considered for targeted therapy of GC patients to improve their survival.
1. Matsuoka T, Yashiro M. Biomarkers of gastric cancer: Current topics and future perspective. World J. Gastroenterol. 2018.
2. Wagner AD, Syn NLX, Moehler M, Grothe W, Yong WP, Tai BC, et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst. Rev. 2017.
3. Bikbov B, Purcell CA, Levey AS, Smith M, Abdoli A, Abebe M, et al. Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020;
4. Baniak N, Senger JL, Ahmed S, Kanthan SC, Kanthan R. Gastric biomarkers: A global review. World J. Surg. Oncol. 2016.
5. Soleyman-Jahi S, Abdirad A, Fallah AA, Ghasemi S, Sadeghi F, Heidari R, et al. Prognostic Significance of Preoperative and Postoperative Plasma Levels of Ghrelin in Gastric Cancer: 3-Year Survival Study. Clin Transl Gastroenterol [Internet]. Nature Publishing Group; 2017;8:e209-10. Available from: http://dx.doi.org/10.1038/ctg.2016.64
6. Akiyama T, Sudo C, Ogawara H, Toyoshima K, Yamamoto T. The product of the human c-erbB-2 gene: A 185-kilodalton glycoprotein with tyrosine kinase activity. Science (80- ). 1986;
7. Jørgensen JT, Hersom M. HER2 as a prognostic marker in gastric cancer - A systematic analysis of data from the literature. J Cancer. 2012;
8. Kim JW, Im SA, Kim M, Cha Y, Lee KH, Keam B, et al. The prognostic significance of HER2 positivity for advanced gastric cancer patients undergoing first-line modified FOLFOX-6 regimen. Anticancer Res. 2012;
9. Janjigian YY, Werner D, Pauligk C, Steinmetz K, Kelsen DP, Jäger E, et al. Prognosis of metastatic gastric and gastroesophageal junction cancer by HER2 status: A European and USA International collaborative analysis. Ann Oncol. 2012;
10. Gómez-Martin C, Garralda E, José Echarri M, Ballesteros A, Arcediano A, Rodríguez-Peralto JL, et al. HER2/neu testing for anti-HER2-based therapies in patients with unresectable and/or metastatic gastric cancer. J Clin Pathol. 2012;
11. Fenoglio-Preiser CM, Wang J, Stemmermann GN, Noffsinger A. TP53 and gastric carcinoma: A review. Hum. Mutat. 2003.
12. Liu G, Xiong D, Zeng J, Chen B, Huang Z. Clinicopathological and prognostic significance of Ki-67 immunohistochemical expression in gastric cancer: A systematic review and meta-analysis. Onco Targets Ther. 2017;
13. Scholzen T, Gerdes J. The Ki-67 protein: From the known and the unknown. J. Cell. Physiol. 2000.
14. Tenderenda M, Rutkowski P, Jesionek-Kupnicka D, Kubiak R. Expression of CD34 in gastric cancer and its correlation with histology, stage, proliferation activity, p53 expression and apoptotic index. Pathol Oncol Res. 2001;
15. Ding S, Li C, Lin S, Yang Y, Liu D, Han Y, et al. Comparative evaluation of microvessel density determined by CD34 or CD105 in benign and malignant gastric lesions. Hum Pathol. 2006;
16. Uefuji K, Ichikura T, Mochizuki H. Cyclooxygenase-2 expression is related to prostaglandin biosynthesis and angiogenesis in human gastric cancer. Clin Cancer Res. 2000;
17. Ren J, Liu J, Sui X. Correlation of COX-2 and MMP-13 expressions with gastric cancer and their effects on prognosis. J BUON. 2019;
18. Honda M, Mori M, Ueo H, Sugimachi K, Akiyoshi T. Matrix metalloproteinase-7 expression in gastric carcinoma. Gut. 1996;
19. Koskensalo S, Mrena J, Wiksten JP, Nordling S, Kokkola A, Hagström J, et al. MMP-7 overexpression is an independent prognostic marker in gastric cancer. Tumor Biol. 2010;
20. Ii M, Yamamoto H, Adachi Y, Maruyama Y, Shinomura Y. Role of matrix metalloproteinase-7 (matrilysin) in human cancer invasion, apoptosis, growth, and angiogenesis. Exp. Biol. Med. 2006.
21. Fuyuhiro Y, Yashiro M, Noda S, Kashiwagi S, Matsuoka J, Doi Y, et al. Clinical significance of vimentin-positive gastric cancer cells. Anticancer Res. 2010;
22. Otsuki S, Inokuchi M, Enjoji M, Ishikawa T, Takagi Y, Kato K, et al. Vimentin expression is associated with decreased survival in gastric cancer. Oncol Rep. 2011;
23. Ko GH, Go S Il, Lee WS, Lee JH, Jeong SH, Lee YJ, et al. Prognostic impact of Ki-67 in patients with gastric cancer-the importance of depth of invasion and histologic differentiation. Med (United States). 2017;96.
24. Habibi A, Ranjbari N, Rahim F, Jazayeri N. Correlation between CD34 marker and clinico-pathologic characteristics of gastric cancer. Int J Cancer Res [Internet]. Science Alert; 2015;11:136–42. Available from: http://dx.doi.org/10.3923/ijcr.2015.136.142
25. Lim HY, Joo HJ, Choi JH, Yi JW, Yang MS, Cho DY, et al. Increased Expression of Cyclooxygenase-2 Protein in Human Gastric Carcinoma Table of Contents P age : A uto ma t ic Z oo m. 2020;3265.
26. Soleyman-Jahi S, Nedjat S, Abdirad A, Hoorshad N, Heidari R, Zendehdel K. Prognostic significance of matrix metalloproteinase-7 in gastric cancer survival: A meta-analysis. PLoS One. 2015;10:1–17.
27. Hwang HJ, Nam SK, Park H, Park Y, Koh J, Na HY, et al. Prediction of TP53 mutations by p53 immunohistochemistry and their prognostic significance in gastric cancer. J Pathol Transl Med. 2020;54:378–86.
28. Zendehdel K, Marzban M, Nahvijou A, Jafari N. Six-fold difference in the stomach cancer mortality rate between northern and southern Iran. Arch Iran Med. 2012;
29. Khedmat H, Panahian M, Mashahdian M, Rajabpour MV, Zendehdel K. Prognostic factors and survival in stomach cancer - Analysis of 15 years of data from a referral hospital in iran and evaluation of international variation. Onkologie. 2011;
30. Bartley AN, Christ J, Fitzgibbons PL, Hamilton SR, Kakar S, Shah MA, et al. Template for reporting results of HER2 (ERBB2) biomarker testing of specimens from patients with adenocarcinoma of the stomach or esophagogastric junction. Arch Pathol Lab Med. 2015;
31. Gnant M, Thomssen C, Harbeck N. St. Gallen/Vienna 2015: A brief summary of the consensus discussion. Breast Care. 2015;10:124–30.
32. Satala CB, Jung I, Stefan-Van Staden RI, Kovacs Z, Molnar C, Bara TB, et al. HER2 heterogeneity in gastric cancer: A comparative study, using two commercial antibodies. J Oncol. 2020;
33. Chen L, Li X, Wang GL, Wang Y, Zhu YY, Zhu J. Clinicopathological significance of overexpression of TSPAN1, KI67 and CD34 in gastric carcinoma. Tumori. 2008;
34. Pietrantonio F, De Braud F, Da Prat V, Perrone F, Pierotti MA, Gariboldi M, et al. A review on biomarkers for prediction of treatment outcome in gastric cancer. Anticancer Res. 2013.
35. Yildirim M, Kaya V, Demirpence O, Gunduz S, Bozcuk H. Prognostic significance of p53 in gastric cancer: A meta-analysis. Asian Pacific J Cancer Prev. 2015;
36. Jung SU, Park KK, Yang SI, Jang HK, Shin YM. Clinicopathological correlations with p53 expression in gastric cancer patients with curative resection. Korean J Clin Oncol. 2014;
37. Maihöfner C, Tegeder I, Euchenhofer C, DeWitt D, Brune K, Bang R, et al. Localization and regulation of cyclo-oxygenase-1 and -2 and neuronal nitric oxide synthase in mouse spinal cord. Neuroscience. 2000;
38. Harris RC, McKanna JA, Akai Y, Jacobson HR, Dubois RN, Breyer MD. Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J Clin Invest. 1994;
39. Maihöfner C, Schlötzer-Schrehardt U, Gühring H, Ulrich Zeilhofer H, Naumann GOH, Pahl A, et al. Expression of cyclooxygenase-1 and -2 in normal and glaucomatous human eyes. Investig Ophthalmol Vis Sci. 2001;
40. Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Annu. Rev. Pharmacol. Toxicol. 1998.
41. Subbaramaiah K, Dannenberg AJ. Cyclooxygenase 2: A molecular target for cancer prevention and treatment. Trends Pharmacol. Sci. 2003.
42. Ghosh N, Chaki R, Mandal V, Mandal SC. Cox-2 as a target for cancer chemotherapy. Pharmacol Reports. 2010;
43. Hu Z, Hu Y, Jiang H. Overexpression of COX-2 and clinicopathological features of gastric cancer: A meta-analysis. Transl Cancer Res. 2020;9:2200–9.
44. Guo Q, Li Q, Wang J, Liu M, Wang Y, Chen Z, et al. A comprehensive evaluation of clinical efficacy and safety of celecoxib in combination with chemotherapy in metastatic or postoperative recurrent gastric cancer patients: A preliminary, three-center, clinical trial study. Medicine (Baltimore). 2019;98:e16234.
45. Luo G, Hu Y, Zhang Z, Wang P, Luo Z, Lin J, et al. Clinicopathologic significance and prognostic value of Ki-67 expression in patients with gastric cancer: A meta-analysis. Oncotarget. 2017;
46. Xiong DD, Zeng CM, Jiang L, Luo DZ, Chen G. Ki-67/MKI67 as a predictive biomarker for clinical outcome in gastric cancer patients: An Updated Meta-analysis and Systematic Review involving 53 Studies and 7078 Patients. J Cancer. 2019;
2. Wagner AD, Syn NLX, Moehler M, Grothe W, Yong WP, Tai BC, et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst. Rev. 2017.
3. Bikbov B, Purcell CA, Levey AS, Smith M, Abdoli A, Abebe M, et al. Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020;
4. Baniak N, Senger JL, Ahmed S, Kanthan SC, Kanthan R. Gastric biomarkers: A global review. World J. Surg. Oncol. 2016.
5. Soleyman-Jahi S, Abdirad A, Fallah AA, Ghasemi S, Sadeghi F, Heidari R, et al. Prognostic Significance of Preoperative and Postoperative Plasma Levels of Ghrelin in Gastric Cancer: 3-Year Survival Study. Clin Transl Gastroenterol [Internet]. Nature Publishing Group; 2017;8:e209-10. Available from: http://dx.doi.org/10.1038/ctg.2016.64
6. Akiyama T, Sudo C, Ogawara H, Toyoshima K, Yamamoto T. The product of the human c-erbB-2 gene: A 185-kilodalton glycoprotein with tyrosine kinase activity. Science (80- ). 1986;
7. Jørgensen JT, Hersom M. HER2 as a prognostic marker in gastric cancer - A systematic analysis of data from the literature. J Cancer. 2012;
8. Kim JW, Im SA, Kim M, Cha Y, Lee KH, Keam B, et al. The prognostic significance of HER2 positivity for advanced gastric cancer patients undergoing first-line modified FOLFOX-6 regimen. Anticancer Res. 2012;
9. Janjigian YY, Werner D, Pauligk C, Steinmetz K, Kelsen DP, Jäger E, et al. Prognosis of metastatic gastric and gastroesophageal junction cancer by HER2 status: A European and USA International collaborative analysis. Ann Oncol. 2012;
10. Gómez-Martin C, Garralda E, José Echarri M, Ballesteros A, Arcediano A, Rodríguez-Peralto JL, et al. HER2/neu testing for anti-HER2-based therapies in patients with unresectable and/or metastatic gastric cancer. J Clin Pathol. 2012;
11. Fenoglio-Preiser CM, Wang J, Stemmermann GN, Noffsinger A. TP53 and gastric carcinoma: A review. Hum. Mutat. 2003.
12. Liu G, Xiong D, Zeng J, Chen B, Huang Z. Clinicopathological and prognostic significance of Ki-67 immunohistochemical expression in gastric cancer: A systematic review and meta-analysis. Onco Targets Ther. 2017;
13. Scholzen T, Gerdes J. The Ki-67 protein: From the known and the unknown. J. Cell. Physiol. 2000.
14. Tenderenda M, Rutkowski P, Jesionek-Kupnicka D, Kubiak R. Expression of CD34 in gastric cancer and its correlation with histology, stage, proliferation activity, p53 expression and apoptotic index. Pathol Oncol Res. 2001;
15. Ding S, Li C, Lin S, Yang Y, Liu D, Han Y, et al. Comparative evaluation of microvessel density determined by CD34 or CD105 in benign and malignant gastric lesions. Hum Pathol. 2006;
16. Uefuji K, Ichikura T, Mochizuki H. Cyclooxygenase-2 expression is related to prostaglandin biosynthesis and angiogenesis in human gastric cancer. Clin Cancer Res. 2000;
17. Ren J, Liu J, Sui X. Correlation of COX-2 and MMP-13 expressions with gastric cancer and their effects on prognosis. J BUON. 2019;
18. Honda M, Mori M, Ueo H, Sugimachi K, Akiyoshi T. Matrix metalloproteinase-7 expression in gastric carcinoma. Gut. 1996;
19. Koskensalo S, Mrena J, Wiksten JP, Nordling S, Kokkola A, Hagström J, et al. MMP-7 overexpression is an independent prognostic marker in gastric cancer. Tumor Biol. 2010;
20. Ii M, Yamamoto H, Adachi Y, Maruyama Y, Shinomura Y. Role of matrix metalloproteinase-7 (matrilysin) in human cancer invasion, apoptosis, growth, and angiogenesis. Exp. Biol. Med. 2006.
21. Fuyuhiro Y, Yashiro M, Noda S, Kashiwagi S, Matsuoka J, Doi Y, et al. Clinical significance of vimentin-positive gastric cancer cells. Anticancer Res. 2010;
22. Otsuki S, Inokuchi M, Enjoji M, Ishikawa T, Takagi Y, Kato K, et al. Vimentin expression is associated with decreased survival in gastric cancer. Oncol Rep. 2011;
23. Ko GH, Go S Il, Lee WS, Lee JH, Jeong SH, Lee YJ, et al. Prognostic impact of Ki-67 in patients with gastric cancer-the importance of depth of invasion and histologic differentiation. Med (United States). 2017;96.
24. Habibi A, Ranjbari N, Rahim F, Jazayeri N. Correlation between CD34 marker and clinico-pathologic characteristics of gastric cancer. Int J Cancer Res [Internet]. Science Alert; 2015;11:136–42. Available from: http://dx.doi.org/10.3923/ijcr.2015.136.142
25. Lim HY, Joo HJ, Choi JH, Yi JW, Yang MS, Cho DY, et al. Increased Expression of Cyclooxygenase-2 Protein in Human Gastric Carcinoma Table of Contents P age : A uto ma t ic Z oo m. 2020;3265.
26. Soleyman-Jahi S, Nedjat S, Abdirad A, Hoorshad N, Heidari R, Zendehdel K. Prognostic significance of matrix metalloproteinase-7 in gastric cancer survival: A meta-analysis. PLoS One. 2015;10:1–17.
27. Hwang HJ, Nam SK, Park H, Park Y, Koh J, Na HY, et al. Prediction of TP53 mutations by p53 immunohistochemistry and their prognostic significance in gastric cancer. J Pathol Transl Med. 2020;54:378–86.
28. Zendehdel K, Marzban M, Nahvijou A, Jafari N. Six-fold difference in the stomach cancer mortality rate between northern and southern Iran. Arch Iran Med. 2012;
29. Khedmat H, Panahian M, Mashahdian M, Rajabpour MV, Zendehdel K. Prognostic factors and survival in stomach cancer - Analysis of 15 years of data from a referral hospital in iran and evaluation of international variation. Onkologie. 2011;
30. Bartley AN, Christ J, Fitzgibbons PL, Hamilton SR, Kakar S, Shah MA, et al. Template for reporting results of HER2 (ERBB2) biomarker testing of specimens from patients with adenocarcinoma of the stomach or esophagogastric junction. Arch Pathol Lab Med. 2015;
31. Gnant M, Thomssen C, Harbeck N. St. Gallen/Vienna 2015: A brief summary of the consensus discussion. Breast Care. 2015;10:124–30.
32. Satala CB, Jung I, Stefan-Van Staden RI, Kovacs Z, Molnar C, Bara TB, et al. HER2 heterogeneity in gastric cancer: A comparative study, using two commercial antibodies. J Oncol. 2020;
33. Chen L, Li X, Wang GL, Wang Y, Zhu YY, Zhu J. Clinicopathological significance of overexpression of TSPAN1, KI67 and CD34 in gastric carcinoma. Tumori. 2008;
34. Pietrantonio F, De Braud F, Da Prat V, Perrone F, Pierotti MA, Gariboldi M, et al. A review on biomarkers for prediction of treatment outcome in gastric cancer. Anticancer Res. 2013.
35. Yildirim M, Kaya V, Demirpence O, Gunduz S, Bozcuk H. Prognostic significance of p53 in gastric cancer: A meta-analysis. Asian Pacific J Cancer Prev. 2015;
36. Jung SU, Park KK, Yang SI, Jang HK, Shin YM. Clinicopathological correlations with p53 expression in gastric cancer patients with curative resection. Korean J Clin Oncol. 2014;
37. Maihöfner C, Tegeder I, Euchenhofer C, DeWitt D, Brune K, Bang R, et al. Localization and regulation of cyclo-oxygenase-1 and -2 and neuronal nitric oxide synthase in mouse spinal cord. Neuroscience. 2000;
38. Harris RC, McKanna JA, Akai Y, Jacobson HR, Dubois RN, Breyer MD. Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J Clin Invest. 1994;
39. Maihöfner C, Schlötzer-Schrehardt U, Gühring H, Ulrich Zeilhofer H, Naumann GOH, Pahl A, et al. Expression of cyclooxygenase-1 and -2 in normal and glaucomatous human eyes. Investig Ophthalmol Vis Sci. 2001;
40. Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Annu. Rev. Pharmacol. Toxicol. 1998.
41. Subbaramaiah K, Dannenberg AJ. Cyclooxygenase 2: A molecular target for cancer prevention and treatment. Trends Pharmacol. Sci. 2003.
42. Ghosh N, Chaki R, Mandal V, Mandal SC. Cox-2 as a target for cancer chemotherapy. Pharmacol Reports. 2010;
43. Hu Z, Hu Y, Jiang H. Overexpression of COX-2 and clinicopathological features of gastric cancer: A meta-analysis. Transl Cancer Res. 2020;9:2200–9.
44. Guo Q, Li Q, Wang J, Liu M, Wang Y, Chen Z, et al. A comprehensive evaluation of clinical efficacy and safety of celecoxib in combination with chemotherapy in metastatic or postoperative recurrent gastric cancer patients: A preliminary, three-center, clinical trial study. Medicine (Baltimore). 2019;98:e16234.
45. Luo G, Hu Y, Zhang Z, Wang P, Luo Z, Lin J, et al. Clinicopathologic significance and prognostic value of Ki-67 expression in patients with gastric cancer: A meta-analysis. Oncotarget. 2017;
46. Xiong DD, Zeng CM, Jiang L, Luo DZ, Chen G. Ki-67/MKI67 as a predictive biomarker for clinical outcome in gastric cancer patients: An Updated Meta-analysis and Systematic Review involving 53 Studies and 7078 Patients. J Cancer. 2019;
| Files | ||
| Issue | Vol 15 No 2 (2023) | |
| Section | Original Articles | |
| Keywords | ||
| Gastric cancer Immunohistochemistry Prognosis Tumor Markers | ||
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How to Cite
1.
Razavirad A, Mohammadnezhad A, Soleymanjahi S, Rismanchi S, Saeedi E, Fallah A, Abdollahi A, Amanpour S, Zendehdel K. Prognostic significance of HER2, p53, Ki67, MVD-CD34, Cox2, MMP7, and vimentin in gastric cancer. Basic Clin Cancer Res. 2024;15(2):67-80.
