EGFR protein overexpression correlates with chromosome 7 polysomy and poor prognostic parameters in clear cell renal cell carcinoma
Tóm tắt
The role of epidermal growth factor (EGF) and its receptor (EGFR) in the pathogenesis and progression of various malignant tumors has long been known, but there is still disagreement concerning prognostic significance of EGFR expression in clear cell renal cell carcinoma (CCRCC). The present study was designed to analyze more objectively the protein EGFR expression in CCRCC and to compare its value with EGFR gene copy number changes and clinicopathologic characteristics including patient survival. The protein EGFR expression was analyzed immunohistochemically on 94 CCRCC, and gene copy number alterations of EGFR by FISH analysis on 41 CCRCC selected according to distinct membrane EGFR staining. Membrane EGFR expression in tumor cells was heterogeneous with respect to the proportion of positive cells and staining intensity. FISH analysis did not reveal EGFR gene amplification, while polysomy of chromosome 7 found in 41% was associated with higher EGFR membrane expression. Moreover, EGFR overexpression was associated with a higher nuclear grade, larger tumor size and shorter patient's survival, while there was no connection with pathological stage. In conclusion, the protein expression of EGFR had an impact on prognosis in patients with CCRCC, while an increased copy number of chromosome 7 could be the possible reason for EGFR protein overexpression in the absence of gene amplification.
Tài liệu tham khảo
Sporn MB, Roberts AB: Autocrine growth factors and cancer. Nature. 1985, 313: 745-747. 10.1038/313745a0.
Wells A: EGF receptor. Int J Biochem Cell Biol. 1999, 31: 637-643. 10.1016/S1357-2725(99)00015-1.
Schlessinger J: Ligand-induced receptor-mediated dimerization and activation of EGF receptor. Cell. 2002, 110: 669-672. 10.1016/S0092-8674(02)00966-2.
Martin V, Mazzucchelli L, Frattini M: An overview of the epidermal growth factor receptor fluorescence in situ hybridisation challenge in tumour pathology. J Clin Pathol. 2009, 62: 314-324. 10.1136/jcp.2008.059592.
Baselga J: EGFR as a target for anticancer therapy-focus on cetuximab. Eur J Cancer. 2001, 37: S16-S22.
Weber F, Fukino k, Sawada T, Williams N, Sweet K, Berena RM, Plass C, Caldes T, Mutter GL, Villalona-Clero MA, Eng C: Variability in organ-specific EGFR mutational spectra in tumor epithelium and stroma may be the biological basis for differential responses to tyrosine kinase inhibitors. Br J Cancer. 2005, 92: 1922-1926. 10.1038/sj.bjc.6602557.
Ono M, Kuwano M: Molecular mechanisms of epidermal growth factor receptor (EGFR) activation and response to gefitinib and other EGFR-targeting drugs. Clin Cancer Res. 2006, 12: 7242-7251. 10.1158/1078-0432.CCR-06-0646.
Langner C, Ratschek M, Rehak , Schips L, Zigeuner R: Are heterogeneous results of EGFR immunoreactivity in renal cell carcinoma related to non-standardised criteria for staining evaluation?. J Clin Pathol. 2004, 57: 773-775. 10.1136/jcp.2003.015743.
Cappuzzo F: EGFR FISH versus mutation: different tests, different end-points. Lung Cancer. 2008, 60: 160-165. 10.1016/j.lungcan.2008.02.008.
Kawahara A, Yamamoto C, Nakashima K, Azuma K, Hattori S, Kashihara M, Aizawa H, Basaki Y, Kuwano M, Kage M, Mitsudomi T, Ono M: Molecular diagnosis of activating EGFR mutations in non-small cell lung cancer using mutation-specific antibodies for immunohistochemical analysis. Clin Cancer Res. 2010, 16 (12): 3163-3170. 10.1158/1078-0432.CCR-09-3239.
Rocha-Lima CM, Soares HP, Raez LE, Singal R: EGFR targeting of solid tumors. Cancer Control. 2007, 14: 295-299.
Venook AP: Epidermal growth factor receptor-targeted treatment for advanced colorectal carcinoma. Cancer. 2005, 103: 2435-2446. 10.1002/cncr.21123.
Normanno N, De Luca A, Bianco C, Strizzi L, Mancino M, Maiello MR, Carotenuto A, De Feo G, Caponigro F, Salomon DS: Epidermal growth factor receptor (EGFR) signalling in cancer. Gene. 2006, 366: 2-16. 10.1016/j.gene.2005.10.018.
Dancey EJ: Epidermal growth factor receptor and epidermal growth factor receptor therapies in renal cell carcinoma: do we need a better mouse trap?. J Clin Oncol. 2004, 22: 2975-2977. 10.1200/JCO.2004.04.934.
Pu YS, Huang CY, Kuo YZ, Kang WY, Liu GY, Huang AM, Yu HJ, Lai MK, Huang SP, Wu WJ, Chiou SJ, Hour TC: Characterization of membranous and cytoplasmic EGFR expression in human normal renal cortex and renal cell carcinoma. J Biomed Sci. 2009, 16: 82. (Published online 2009 September 12. doi: 10.1186/1423-0127-16-82)
Ravaud A, Clermont H, Pasticier G, Smith D, Vendrely V, Maire JP: Epithelial growth factor receptor (EGFR) pathway and renal cell carcinoma. Targ Oncol. 2007, 2: 99-105. 10.1007/s11523-007-0044-7.
Hassan S, Ferrario C, Mamo A, Basik M: Tissue microarrays: emerging standard for biomarker validation. Curr Opin Biotechnol. 2008, 19: 19-25. 10.1016/j.copbio.2007.10.009.
WHO Classification of Tumors. Pathology and Genetics of Tumors of the Urinary System and Male Genital Organs. Edited by: Eble JN, Sauter G, Epstein JI, Sesterhenn IA. 2004, Lyon, France: IARC Press, 9-87.
TNM Classification of Malignant Tumours. Edited by: Sobin L, Gospodarowicz M, Wittekind C. 2009, Singapore, Republic of Singapore: Wiley-Blackwell, 255-258.
Fuhrman SA, Lasky LC, Limas C: Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol. 1982, 6: 655-663. 10.1097/00000478-198210000-00007.
Moch H, Sauter G, Gasser TC, Bubendorf L, Richter J, Presti JC, Waldman FM, Mihatsch MJ: EGF-r gene copy number changes in renal cell carcinoma detected by fluorescence in situ hybridization. J Pathol. 1998, 184: 424-429. 10.1002/(SICI)1096-9896(199804)184:4<424::AID-PATH1223>3.0.CO;2-A.
Saltz LB, Meropol NJ, Loehrer PJ: Phase II trial of cetuximab in patients with refractory colorectal cancer that express the epidermal growth factor receptor. J Clin Oncol. 2004, 22: 1201-1208. 10.1200/JCO.2004.10.182.
Cohen D, Lane B, Jin T, Magi-Galluzzi C, Finke J, Rini BI, Bukowski RM, Zhou M: The prognostic significance of epidermal growth factor receptor expression in clear-cell renal cell carcinoma: a call for standardized methods for immunohistochemical evaluation. Clin Genitourin Cancer. 2007, 5: 264-270. 10.3816/CGC.2007.n.002.
Michael A, Relph K, Havranek E, Anderson C, Polychronis A, Corbishley C, Pandha H: Prognostic Impact of p53, EGFR And HER2/Neu Proteins on renal cell carcinoma. The Internet Journal of Urology. 2006, 4: [http://www.ispub.com/journal/the_internet_journal_of_urology/volume_4_number_1]
Kallio JP, Hirvikoski P, Helin H, Kellokumpu-Lehtinen P, Luukkaala T, Tammela TLJ, Martikainen PM: Membranous location of EGFR immunostaining is associated with good prognosis in renal cell carcinoma. Br J Cancer. 2003, 89: 1266-1269. 10.1038/sj.bjc.6601241.
Hofmockel G, Reiss S, Bassukas ID, Dammrich J: Epidermal growth factor family and renal cell carcinoma: overexpression and prognostic impact. Eur Urol. 1997, 31: 478-484.
Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF: American Society of Clinical Oncology; College of American Pathologists. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007, 25 (1): 118-145.
Lager DJ, Slagel DD, Palechek PL: The expression of epidermal growth factor receptor and transforming growth factor alfa in renal cell carcinoma. Mod Pathol. 1994, 7: 544-548.
Merseburger AS, Hennenlotter J, Simon P, Kruck S, Koch E, Horstmann M, Kuehs U, Küfer R, Stenzl A, Kuczyk MA: Membranous expression and prognostic implications of epidermal growth factor receptor protein in human renal cell cancer. Anticancer Res. 2005, 25: 1901-1907.
Zigler Villares, Blehm M, Bogdan C, McConkey D, Colin D, Bar-Eli M: Targeting EGFR in bladder cancer. World J Urol. 2007, 25: 573-579. 10.1007/s00345-007-0202-7.
Uhlman DL, Nguyen P, Manivel JC, Zhang G, Hagen K, Fraley E, Aeppli D, Niehans GA: Epidermal growth factor receptor and transforming growth factor alpha expression in papillary and nonpapillary renal cell carcinoma: correlation with metastatic behavior and prognosis. Clin Cancer Res. 1995, 8: 913-920.
Stumm G, Eberwein S, Rostock-Wolf S, Stein H, Pomer S, Schlegel J, Waldherr R: Concomitant overexpression of the EGFR and erbB-2 genes in renal cell carcinoma (RCC) is correlated with dedifferentiation and metastasis. Int J Cancer. 1996, 69: 17-22. 10.1002/(SICI)1097-0215(19960220)69:1<17::AID-IJC4>3.0.CO;2-Z.
Lee S, An J, Kim A, Kim YS, Kim I: The EGFR protein expression and the gene copy number changes in renal cell carcinomas. Korean J Pathol. 2009, 43: 413-419. 10.4132/KoreanJPathol.2009.43.5.413.