EGFR protein overexpression correlates with chromosome 7 polysomy and poor prognostic parameters in clear cell renal cell carcinoma

Journal of Biomedical Science

Nives Jonjić²  Blaženka Grahovac²  Anton Maričić¹  Ita Hadžisejdić²  Koviljka Matušan Ilijaš²  Gordana Đorđević² 

[1] Department of Urology, Rijeka University Hospital Centre, Krešimirova 42, Rijeka 51000, Croatia;Department of Pathology, School of Medicine, University of Rijeka, B. Branchetta 20, Rijeka 51000, Croatia

关键词: Prognosis;    Fluorescence;    In Situ Hybridization;    EGFR;    Chromosome 7;    Renal cell;    Carcinoma;   

Others  :  825289
DOI  :  10.1186/1423-0127-19-40

 received in 2011-06-10, accepted in 2012-04-05,  发布年份 2012

【 摘 要 】

Background

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.

Methods

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.

Results

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.

Conclusion

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.

【 授权许可】

   
2012 Đorđević et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Sporn MB, Roberts AB: Autocrine growth factors and cancer. Nature 1985, 313:745-747.
• [2]Wells A: EGF receptor. Int J Biochem Cell Biol 1999, 31:637-643.
• [3]Schlessinger J: Ligand-induced receptor-mediated dimerization and activation of EGF receptor. Cell 2002, 110:669-672.
• [4]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.
• [5]Baselga J: EGFR as a target for anticancer therapy-focus on cetuximab. Eur J Cancer 2001, 37:S16-S22.
• [6]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.
• [7]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.
• [8]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.
• [9]Cappuzzo F: EGFR FISH versus mutation: different tests, different end-points. Lung Cancer 2008, 60:160-165.
• [10]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.
• [11]Rocha-Lima CM, Soares HP, Raez LE, Singal R: EGFR targeting of solid tumors. Cancer Control 2007, 14:295-299.
• [12]Venook AP: Epidermal growth factor receptor-targeted treatment for advanced colorectal carcinoma. Cancer 2005, 103:2435-2446.
• [13]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.
• [14]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.
• [15]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)
• [16]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.
• [17]Hassan S, Ferrario C, Mamo A, Basik M: Tissue microarrays: emerging standard for biomarker validation. Curr Opin Biotechnol 2008, 19:19-25.
• [18]Eble JN, Sauter G, Epstein JI, Sesterhenn IA (Eds): WHO Classification of Tumors. Pathology and Genetics of Tumors of the Urinary System and Male Genital Organs Lyon, France: IARC Press; 2004:9-87.
• [19]Sobin L, Gospodarowicz M, Wittekind C (Eds): TNM Classification of Malignant Tumours. Singapore, Republic of Singapore: Wiley-Blackwell; 2009:255-258.
• [20]Fuhrman SA, Lasky LC, Limas C: Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982, 6:655-663.
• [21]Moch H, Sauter G, Gasser TC, Bubendorf L, Richter J, Presti JC Jr, 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.
• [22]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.
• [23]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.
• [24]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. [http:/ / www.ispub.com/ journal/ the_internet_journal_of_urology/ volume_4_number_1] webciteThe Internet Journal of Urology 2006., 4
• [25]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.
• [26]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.
• [27]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.
• [28]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.
• [29]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.
• [30]Zigler VillaresGJ, Blehm M, Bogdan C, McConkey D, Colin D, Bar-Eli M: Targeting EGFR in bladder cancer. World J Urol 2007, 25:573-579.
• [31]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.
• [32]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.
• [33]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.