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Published in: International Journal of Clinical Oncology 2/2013

01-04-2013 | Original Article

Clinical impact of c-Met expression and its gene amplification in hepatocellular carcinoma

Authors: Shunsuke Kondo, Hidenori Ojima, Hitoshi Tsuda, Jun Hashimoto, Chigusa Morizane, Masafumi Ikeda, Hideki Ueno, Kenji Tamura, Kazuaki Shimada, Yae Kanai, Takuji Okusaka

Published in: International Journal of Clinical Oncology | Issue 2/2013

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Abstract

Background

c-Met is an oncogene encoding a receptor for hepatocyte growth factor and, as such, plays a key role in hepatocellular carcinomas (HCC). We evaluated c-Met protein expression and its gene amplification in order to assess whether they were related to tumor recurrence and survival rates among patients who had undergone tumor resection.

Methods

We used the polymer-based method to perform an immunohistochemistry analysis of c-Met expression on 59 formalin-fixed, paraffin-embedded sections of surgical specimens. c-Met gene amplification was investigated with fluorescence in-situ hybridization. Kaplan–Meier methods and Cox proportional hazards models were used to investigate relationships between c-Met expression, patient characteristics, tumor recurrence, and survival.

Results

c-Met expression was associated with portal vein invasion (p = 0.006). Recurrence-free survival rates were significantly lower in patients with high levels of c-Met expression (p < 0.001). However, c-Met expression levels did not significantly affect overall survival rates (p = 0.12). Only 1 patient was found to have c-Met gene amplification; 22 patients were found to have aneuploidy of chromosome 7, on which the c-Met gene is located. Tumors with chromosome 7 polysomy tended to have higher levels of c-Met expression than those with chromosome 7 monosomy or disomy, but this difference was not statistically significant.

Conclusion

Although c-Met expression was not significantly associated with c-Met gene amplification, it may be a useful predictive marker of recurrence in resected HCC patients.
Literature
1.
go back to reference Parkin DM, Bray F, Ferlay J et al (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108PubMedCrossRef Parkin DM, Bray F, Ferlay J et al (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108PubMedCrossRef
2.
go back to reference Donato F, Boffetta P, Puoti M (1998) A meta-analysis of epidemiological studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma. Int J Cancer 75:347–354PubMedCrossRef Donato F, Boffetta P, Puoti M (1998) A meta-analysis of epidemiological studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma. Int J Cancer 75:347–354PubMedCrossRef
3.
go back to reference Furge KA, Zhang YW, Vande Woude GF (2000) Met receptor tyrosine kinase: enhanced signaling through adapter proteins. Oncogene 19:5582–5589PubMedCrossRef Furge KA, Zhang YW, Vande Woude GF (2000) Met receptor tyrosine kinase: enhanced signaling through adapter proteins. Oncogene 19:5582–5589PubMedCrossRef
4.
go back to reference Kaposi-Novak P, Lee JS, Gomez-Quiroz L et al (2006) Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype. J Clin Invest 116:1582–1595PubMedCrossRef Kaposi-Novak P, Lee JS, Gomez-Quiroz L et al (2006) Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype. J Clin Invest 116:1582–1595PubMedCrossRef
5.
go back to reference Okuda K, Ohtsuki T, Obata H et al (1985) Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients. Cancer 56:918–928PubMedCrossRef Okuda K, Ohtsuki T, Obata H et al (1985) Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients. Cancer 56:918–928PubMedCrossRef
6.
go back to reference Chevret S, Trinchet JC, Mathieu D et al (1999) A new prognostic classification for predicting survival in patients with hepatocellular carcinoma. Groupe d’Etude et de Traitement du Carcinome Hepatocellulaire. J Hepatol 31:133–141PubMedCrossRef Chevret S, Trinchet JC, Mathieu D et al (1999) A new prognostic classification for predicting survival in patients with hepatocellular carcinoma. Groupe d’Etude et de Traitement du Carcinome Hepatocellulaire. J Hepatol 31:133–141PubMedCrossRef
7.
go back to reference Iizuka N, Oka M, Yamada-Okabe H et al (2003) Oligonucleotide microarray for prediction of early intrahepatic recurrence of hepatocellular carcinoma after curative resection. Lancet 361:923–929PubMedCrossRef Iizuka N, Oka M, Yamada-Okabe H et al (2003) Oligonucleotide microarray for prediction of early intrahepatic recurrence of hepatocellular carcinoma after curative resection. Lancet 361:923–929PubMedCrossRef
8.
go back to reference Yoshioka S, Takemasa I, Nagano H et al (2009) Molecular prediction of early recurrence after resection of hepatocellular carcinoma. Eur J Cancer 45:881–889PubMedCrossRef Yoshioka S, Takemasa I, Nagano H et al (2009) Molecular prediction of early recurrence after resection of hepatocellular carcinoma. Eur J Cancer 45:881–889PubMedCrossRef
9.
go back to reference Miyamoto M, Ojima H, Iwasaki M et al (2011) Prognostic significance of overexpression of c-Met oncoprotein in cholangiocarcinoma. Br J Cancer 105:131–138PubMedCrossRef Miyamoto M, Ojima H, Iwasaki M et al (2011) Prognostic significance of overexpression of c-Met oncoprotein in cholangiocarcinoma. Br J Cancer 105:131–138PubMedCrossRef
10.
go back to reference Cappuzzo F, Janne PA, Skokan M et al (2009) MET increased gene copy number and primary resistance to gefitinib therapy in non-small-cell lung cancer patients. Ann Oncol 20:298–304PubMedCrossRef Cappuzzo F, Janne PA, Skokan M et al (2009) MET increased gene copy number and primary resistance to gefitinib therapy in non-small-cell lung cancer patients. Ann Oncol 20:298–304PubMedCrossRef
11.
go back to reference Birchmeier C, Birchmeier W, Gherardi E et al (2003) Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4:915–925PubMedCrossRef Birchmeier C, Birchmeier W, Gherardi E et al (2003) Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4:915–925PubMedCrossRef
12.
go back to reference Liu X, Yao W, Newton RC et al (2008) Targeting the c-MET signaling pathway for cancer therapy. Expert Opin Investig Drugs 17:997–1011PubMedCrossRef Liu X, Yao W, Newton RC et al (2008) Targeting the c-MET signaling pathway for cancer therapy. Expert Opin Investig Drugs 17:997–1011PubMedCrossRef
13.
go back to reference Comoglio PM, Giordano S, Trusolino L (2008) Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nat Rev Drug Discov 7:504–516PubMedCrossRef Comoglio PM, Giordano S, Trusolino L (2008) Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nat Rev Drug Discov 7:504–516PubMedCrossRef
14.
go back to reference Ueki T, Fujimoto J, Suzuki T et al (1997) Expression of hepatocyte growth factor and its receptor, the c-met proto-oncogene, in hepatocellular carcinoma. Hepatology 25:619–623PubMedCrossRef Ueki T, Fujimoto J, Suzuki T et al (1997) Expression of hepatocyte growth factor and its receptor, the c-met proto-oncogene, in hepatocellular carcinoma. Hepatology 25:619–623PubMedCrossRef
15.
go back to reference Ke AW, Shi GM, Zhou J et al (2009) Role of overexpression of CD151 and/or c-Met in predicting prognosis of hepatocellular carcinoma. Hepatology 49:491–503PubMedCrossRef Ke AW, Shi GM, Zhou J et al (2009) Role of overexpression of CD151 and/or c-Met in predicting prognosis of hepatocellular carcinoma. Hepatology 49:491–503PubMedCrossRef
16.
go back to reference 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 85:1894–1902PubMed 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 85:1894–1902PubMed
17.
go back to reference Di Renzo MF, Olivero M, Giacomini A et al (1995) Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal cancer. Clin Cancer Res 1:147–154PubMed Di Renzo MF, Olivero M, Giacomini A et al (1995) Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal cancer. Clin Cancer Res 1:147–154PubMed
18.
go back to reference Cappuzzo F, Marchetti A, Skokan M et al (2009) Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. J Clin Oncol 27:1667–1674PubMedCrossRef Cappuzzo F, Marchetti A, Skokan M et al (2009) Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. J Clin Oncol 27:1667–1674PubMedCrossRef
19.
go back to reference Engelman JA, Zejnullahu K, Mitsudomi T et al (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316:1039–1043PubMedCrossRef Engelman JA, Zejnullahu K, Mitsudomi T et al (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316:1039–1043PubMedCrossRef
20.
go back to reference Boix L, Rosa JL, Ventura F et al (1994) c-met mRNA overexpression in human hepatocellular carcinoma. Hepatology 19:88–91PubMedCrossRef Boix L, Rosa JL, Ventura F et al (1994) c-met mRNA overexpression in human hepatocellular carcinoma. Hepatology 19:88–91PubMedCrossRef
21.
go back to reference Schmidt L, Duh FM, Chen F et al (1997) Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet 16:68–73PubMedCrossRef Schmidt L, Duh FM, Chen F et al (1997) Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet 16:68–73PubMedCrossRef
22.
go back to reference Schmidt L, Junker K, Nakaigawa N et al (1999) Novel mutations of the MET proto-oncogene in papillary renal carcinomas. Oncogene 18:2343–2350PubMedCrossRef Schmidt L, Junker K, Nakaigawa N et al (1999) Novel mutations of the MET proto-oncogene in papillary renal carcinomas. Oncogene 18:2343–2350PubMedCrossRef
23.
go back to reference Park WS, Dong SM, Kim SY et al (1999) Somatic mutations in the kinase domain of the Met/hepatocyte growth factor receptor gene in childhood hepatocellular carcinomas. Cancer Res 59:307–310PubMed Park WS, Dong SM, Kim SY et al (1999) Somatic mutations in the kinase domain of the Met/hepatocyte growth factor receptor gene in childhood hepatocellular carcinomas. Cancer Res 59:307–310PubMed
24.
go back to reference Di Renzo MF, Olivero M, Martone T et al (2000) Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas. Oncogene 19:1547–1555PubMedCrossRef Di Renzo MF, Olivero M, Martone T et al (2000) Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas. Oncogene 19:1547–1555PubMedCrossRef
25.
go back to reference Krishnamurti U, Hammers JL, Atem FD et al (2009) Poor prognostic significance of unamplified chromosome 17 polysomy in invasive breast carcinoma. Mod Pathol 22:1044–1048PubMedCrossRef Krishnamurti U, Hammers JL, Atem FD et al (2009) Poor prognostic significance of unamplified chromosome 17 polysomy in invasive breast carcinoma. Mod Pathol 22:1044–1048PubMedCrossRef
Metadata
Title
Clinical impact of c-Met expression and its gene amplification in hepatocellular carcinoma
Authors
Shunsuke Kondo
Hidenori Ojima
Hitoshi Tsuda
Jun Hashimoto
Chigusa Morizane
Masafumi Ikeda
Hideki Ueno
Kenji Tamura
Kazuaki Shimada
Yae Kanai
Takuji Okusaka
Publication date
01-04-2013
Publisher
Springer Japan
Published in
International Journal of Clinical Oncology / Issue 2/2013
Print ISSN: 1341-9625
Electronic ISSN: 1437-7772
DOI
https://doi.org/10.1007/s10147-011-0361-9

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