Abstract
Purpose
Identification of critical genes which play pivotal roles in controlling tumor growth and survival will establish the basis for developing therapeutic targets. In this study, we focused on frequencies of EGFR, ErbB2 and MET gene amplification in gastric cancer patients to develop personalized medicine to improve the treatment.
Method
EGFR, ErbB2 and MET gene amplification, and mRNA expression were analyzed by the quantitative Real-Time PCR in paraffin-embedded samples from 115 patients with gastric cancer.
Results
EGFR, ErbB2 and MET genes were amplified in 11.3 % (13/115), 6.1 % (7/115) and 19.1 % (22/115) of cancerous specimens, respectively. The correlation coefficient test clearly indicated that gene amplification in these three genes was positively correlated with mRNA transcription (EGFR: R = 0.631, p = 0.009; ErbB2: R = 0.652, p = 0.023; MET: R = 0.715, p < 0.001). EGFR and MET gene amplification was significantly associated with Ki-67 MI (p = 0.022 and p = 0.015). MET amplification was also significantly associated with age of ≥60 years (p = 0.021) and tumor size of ≥5 cm (p = 0.032). MET amplification, but not EGFR and ErbB2, was a significant prognostic factor in poor survival among patients with gastric cancer.
Conclusions
EGFR, ErbB2 and MET genes are frequently amplified in gastric carcinoma. EGFR, ErbB2 and MET gene amplification is positively correlated with mRNA transcription. MET gene amplification correlates with a poor prognosis and poor survival in gastric carcinomas.
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References
Al-Batran S-E, Hartmann JT, Hofheinz R et al (2008) Biweekly fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for patients with metastatic adenocarcinoma of the stomach or esophagogastric junction: a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol 19:1882–1887. doi:10.1093/annonc/mdn403
Albertson DG (2006) Gene amplification in cancer. Trends Genet 22:447–455. doi:10.1016/j.tig.2006.06.007
Arteaga CL (2002) Epidermal growth factor receptor dependence in human tumors: more than just expression? Oncologist 7(Suppl 4):31–39. doi:10.1634/theoncologist.7-suppl_4-31
Atmaca A, Werner D, Pauligk C et al (2012) The prognostic impact of epidermal growth factor receptor in patients with metastatic gastric cancer. BMC Cancer 12:524. doi:10.1186/1471-2407-12-524
Bang Y-J, Van Cutsem E, Feyereislova A et al (2010) Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376:687–697. doi:10.1016/S0140-6736(10)61121-X
Beroukhim R, Mermel CH, Porter D et al (2010) The landscape of somatic copy-number alteration across human cancers. Nature 463:899–905. doi:10.1038/nature08822
Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF (2003) Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4:915–925. doi:10.1038/nrm1261
Casalini P, Iorio MV, Galmozzi E, Ménard S (2004) Role of HER receptors family in development and differentiation. J Cell Physiol 200:343–350. doi:10.1002/jcp.20007
Chen JD, Kearns S, Porter T et al (2001) MET mutation and familial gastric cancer. J Med Genet 38:E26. doi:10.1136/jmg.38.8.e26
Cunningham D, Okines AFC, Ashley S (2010) Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 362:858–859. doi:10.1056/NEJMc0911925
Galizia G, Lieto E, Orditura M et al (2007) Epidermal growth factor receptor (EGFR) expression is associated with a worse prognosis in gastric cancer patients undergoing curative surgery. World J Surg 31:1458–1468. doi:10.1007/s00268-007-9016-4
Gamboa-Dominguez A, Dominguez-Fonseca C, Quintanilla-Martinez L et al (2004) Epidermal growth factor receptor expression correlates with poor survival in gastric adenocarcinoma from Mexican patients: a multivariate analysis using a standardized immunohistochemical detection system. Mod Pathol 17:579–587. doi:10.1038/modpathol.3800085
García I, Vizoso F, Martín A et al (2003) Clinical significance of the epidermal growth factor receptor and HER2 receptor in resectable gastric cancer. Ann Surg Oncol 10:234–241. doi:10.1245/ASO.2003.05.010
Graziano F, Galluccio N, Lorenzini P et al (2011) Genetic activation of the MET pathway and prognosis of patients with high-risk, radically resected gastric cancer. J Clin Oncol 29:4789–4795. doi:10.1200/JCO.2011.36.7706
Huang W-T, Chuang S-S (2013) High MET gene copy number predicted poor prognosis in primary intestinal diffuse large B-cell lymphoma. Diagn Pathol 8:16. doi:10.1186/1746-1596-8-16
Jemal A, Bray F, Center MM et al (2011) Global cancer statistics. CA Cancer J Clin 61:69–90. doi:10.3322/caac.20107
Junttila TT, Laato M, Vahlberg T et al (2003) Identification of patients with transitional cell carcinoma of the bladder overexpressing ErbB2, ErbB3, or specific ErbB4 isoforms: real-time reverse transcription-PCR analysis in estimation of ErbB receptor status from cancer patients. Clin Cancer Res 9:5346–5357
Kato H, Arao T, Matsumoto K et al (2013) Gene amplification of EGFR, HER2, FGFR2 and MET in esophageal squamous cell carcinoma. Int J Oncol 42:1151–1158. doi:10.3892/ijo.2013.1830
Kawakami H, Okamoto I, Arao T et al (2013) MET amplification as a potential therapeutic target in gastric cancer. Oncotarget 4:9–17
Kim MA, Lee HS, Lee HE et al (2008) EGFR in gastric carcinomas: prognostic significance of protein overexpression and high gene copy number. Histopathology 52:738–746. doi:10.1111/j.1365-2559.2008.03021.x
Kim J-S, Kim M-A, Kim TM et al (2009) Biomarker analysis in stage III-IV (M0) gastric cancer patients who received curative surgery followed by adjuvant 5-fluorouracil and cisplatin chemotherapy: epidermal growth factor receptor (EGFR) associated with favourable survival. Br J Cancer 100:732–738. doi:10.1038/sj.bjc.6604936
Kuniyasu H, Yasui W, Yokozaki H et al (1993) Aberrant expression of c-met mRNA in human gastric carcinomas. Int J Cancer 55:72–75
Lee JH, Han SU, Cho H et al (2000) A novel germ line juxtamembrane Met mutation in human gastric cancer. Oncogene 19:4947–4953
Lee J, Seo JW, Jun HJ et al (2011) Impact of MET amplification on gastric cancer: possible roles as a novel prognostic marker and a potential therapeutic target. Oncol Rep 25:1517–1524. doi:10.3892/or.2011.1219
Lee HE, Kim MA, Lee HS et al (2012) MET in gastric carcinomas: comparison between protein expression and gene copy number and impact on clinical outcome. Br J Cancer 107:325–333. doi:10.1038/bjc.2012.237
Lieto E, Ferraraccio F, Orditura M et al (2008) Expression of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) is an independent prognostic indicator of worse outcome in gastric cancer patients. Ann Surg Oncol 15:69–79. doi:10.1245/s10434-007-9596-0
Liu X, Newton RC, Scherle PA (2010) Developing c-MET pathway inhibitors for cancer therapy: progress and challenges. Trends Mol Med 16:37–45. doi:10.1016/j.molmed.2009.11.005
Matsubara J, Yamada Y, Nakajima TE et al (2008) Clinical significance of insulin-like growth factor type 1 receptor and epidermal growth factor receptor in patients with advanced gastric cancer. Oncology 74:76–83. doi:10.1159/000139127
Matsumoto K, Arao T, Hamaguchi T et al (2012) FGFR2 gene amplification and clinicopathological features in gastric cancer. Br J Cancer 106:727–732. doi:10.1038/bjc.2011.603
Nakajima M, Sawada H, Yamada Y et al (1999) The prognostic significance of amplification and overexpression of c-met and c-erb B-2 in human gastric carcinomas. Cancer 85:1894–1902
Park WS, Oh RR, Kim YS et al (2000) Absence of mutations in the kinase domain of the Met gene and frequent expression of Met and HGF/SF protein in primary gastric carcinomas. Apmis 108:195–200
Sakai K, Mori S, Kawamoto T et al (1986) Expression of epidermal growth factor receptors on normal human gastric epithelia and gastric carcinomas. J Natl Cancer Inst 77:1047–1052. doi:10.1093/jnci/77.5.1047
Seruca R, Suijkerbuijk RF, Gärtner F et al (1995) Increasing levels of MYC and MET co-amplification during tumor progression of a case of gastric cancer. Cancer Genet Cytogenet 82:140–145. doi:10.1016/0165-4608(95)00033-L
Song HS, Do YR, Kim IH et al (2004) Prognostic significance of immunohistochemical expression of EGFR and C-erbB-2 oncoprotein in curatively resected gastric cancer. Cancer Res Treat 36:240–245. doi:10.4143/crt.2004.36.4.240
Stuart D, Sellers WR (2009) Linking somatic genetic alterations in cancer to therapeutics. Curr Opin Cell Biol 21:304–310. doi:10.1016/j.ceb.2009.02.001
Tahara E (1995) Genetic alterations in human gastrointestinal cancers. The application to molecular diagnosis. Cancer 75:1410–1417
Takeda M, Arao T, Yokote H et al (2007) AZD2171 shows potent antitumor activity against gastric cancer over-expressing fibroblast growth factor receptor 2/keratinocyte growth factor receptor. Clin Cancer Res 13:3051–3057. doi:10.1158/1078-0432.CCR-06-2743
Tsujimoto H, Sugihara H, Hagiwara A, Hattori T (1997) Amplification of growth factor receptor genes and DNA ploidy pattern in the progression of gastric cancer. Virchows Arch 431:383–389. doi:10.1007/s004280050115
Van Cutsem E, Moiseyenko VM, Tjulandin S et al (2006) Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol 24:4991–4997. doi:10.1200/JCO.2006.06.8429
Vogel CL, Cobleigh MA, Tripathy D et al (2002) Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20:719–726. doi:10.1200/JCO.20.3.719
Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2:127–137. doi:10.1038/35052073
Yk W, Gao CF, Yun T et al (2011) Assessment of ERBB2 and EGFR gene amplification and protein expression in gastric carcinoma by immunohistochemistry and fluorescence in situ hybridization. Mol Cytogenet 4:14. doi:10.1186/1755-8166-4-14
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This study supported by a grant from the Research and Technology Department in Mazandaran University of Medical Sciences.
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Janbabai, G., Oladi, Z., Farazmandfar, T. et al. The prognostic impact of EGFR, ErbB2 and MET gene amplification in human gastric carcinomas as measured by quantitative Real-Time PCR. J Cancer Res Clin Oncol 141, 1945–1952 (2015). https://doi.org/10.1007/s00432-015-1965-7
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DOI: https://doi.org/10.1007/s00432-015-1965-7