Promoter hypermethylation of tissue specific tumor supressor genes and point mutation in K-ras, c-myc proto-oncogenes in urinary (transitional cell) bladder carcinoma

Oztürk Ozdemir, Esin Yildiz, Semih Ayan, Eylem Gul, Gökhan Gokce, Fazilet Yildiz, Binnur Koksal

.

DOI: 10.4236/health.2010.28128                

Abstract

In a total of 83 UN specimens were investigated for proto-oncogene mutations, tumor supressor genes promoter methylation status and c-myc and Ki-67 expression. Point mutations in c-myc were detected in cases with high grade and proliferation index. Mutated K-ras proto-onco- gene profiles were detected in 17 (21%) tumoral spiecemens that examined. Tumor specimens were also showed hypermethylated promoter domain for the SFRP2, MGMT tumor supressor genes. These findings showed the combine effect of mutated c-myc and K-ras oncogene and epigenetic inactivation of tissue specific tumor supressor genes (TS) play a crucial role in tumor progression and recurrence in UN carcinogenesis.

Keywords

C-myc; K-ras; Ki-67; Urinary Bladder; Urothelial Neoplasms; Promoter Hypermethylation; Tumor Supressor Genes

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Guo, M., Pollan, M., Herman, J.G. and Esteller, M. (2003) A systematic profile of DNA methylation in human cancer cell lines. Cancer Research, 63(5), 1114-1123.
[2]	Nesb?t, C.E., Tersak, J.M. and Procchown?k, E.V. (1999) MYC oncogenes and human neoplastic disease. Oncogene, 18(9), 3004-3016.
[3]	Plesec, T.P. and Hunt, J.L. (2009) KRAS mutation testing in colorectal cancer. Advances in Anatomic Pathology, 16(4), 196-203.
[4]	Heinemann, V., Stintzing, S., Kircher, T. and Jung, A. (2009) Clinical relevance of EGFR and KRAS status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR. Cancer Treatment Reviews, 35(3), 262-271.
[5]	Schmid, K., Oehl, N., Wrba, F., Pirker, R., Pirker, C. and Filipits, M. (2009) EGFR/KRAS/BRAF mutations in primary lung adenocarcinomas and corresponding loco- regional lymph node metastases. Clinical Cancer Research, 15(14), 4554-4560.
[6]	Bournet, B., Souque, A., Senesse, P., Assenat, E., Barthet, M., Lesavre, N., Aubert, A., O’Toole, D., Hammel, P., Levy, P., Ruszniewski, P., Bouisson, M., Escourrou, J., Cordelier, P. and Buscail, L. (2009) Endoscopic ultrasound-guided fine-needle aspiration biopsy coupled with KRAS mutation assay to distinguish pancreatic cancer from pseudotumoral chronic pancreatitis. Endoscopy, 41(6), 552-557.
[7]	Ellis, L., Atadja, P.W. and Johnstone, R.W. (2009) Epigenetics in cancer: Targeting chromatin modifications. Molecular Cancer Therapeutics, 8(6), 1409-1420.
[8]	Ballestar, E. and Esteller, M. (2008) Epigenetic gene regulation in cancer. Advances in Genetics, 61, 247-267.
[9]	Mueller, W.C. and Von Deimling, A. (2009) Gene regulation by methylation. Recent Results in Cancer Research, 171, 217-239.
[10]	Marsit, C.J., McClean, M.D., Furniss, C.S. and Kelsey, K.T. (2006) Epigenetic inactivation of the SFRP genes is associated with drinking, smoking and HPV in head and neck squamous cell carcinoma. International Journal of Cancer, 119(8), 1761-1766.
[11]	Nojima, M., Suzuki, H., Toyota, M., Watanabe, Y., Maruyama, R., Sasaki, S., Sasaki, Y., Mita, H., Nishikawa, N., Yamaguchi, K., Hirata, K., Itoh, F., Tokino, T., Mori, M., Imai, K. and Shinomura, Y. (2007) Frequent epigenetic inactivation of SFRP genes and constitutive activation of Wnt signaling in gastric cancer. Oncogene, 26(32), 4699-46713.
[12]	Shih, Y.L., Hsieh, C.B., Lai, H.C., Yan, M.D., Hsieh, T.Y., Chao, Y.C. and Lin, Y.W. (2007) SFRP1 suppressed hepatoma cells growth through Wnt canonical signaling pathway. International Journal of Cancer, 121(5), 1028- 1035.
[13]	Krtolica, K., Krajnovic, M., Knezevic, S.U., Babic, D., Jovanovic, D. and Dimitriyevic, B. (2007) Comethilation of P16 and MGMT genes in colorectal carcinoma: Correlation with clinopathological features and prognostic value. World Journal of Gastroenterology, 28(13), 1187- 1194.
[14]	Wales, M.M., Biel, M.A., Deiry, W., Nelkin, B.D., Issa, J.P., Cavenee, W.K., Kuerbitz, S.J. and Baylin, S.B. (1995) p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3. Nature Medicine, 1(6), 570-577.
[15]	Lin, Y., Stevens, C., Harrison, B., Pathuri, S., Amin, E. and Hupp, T.R. (2009) The alternative splice variant of DAPK-1, s-DAPK-1, induces proteasome-independent DAPK-1 destabilization. Molecular and Cellular Biochemistry, 328(1-2), 101-107.
[16]	Anjum, R., Roux, P.P., Ballif, B.A., Gygi, S.P. and Blenis, J. (2005) The tumor suppressor DAP kinase Is a target of RSK-mediated survival signaling. Current Biology, 15(9), 1762-1767.
[17]	Raveh, T. and Kimchi, A. (2001) DAP kinase—A proapoptotic gene that functions as a tumor suppressor. Experimental Cell Research, 264(1), 185-192.
[18]	Baffa, R., Letko, J., McClung, C., LeNo?r, J., Vecch?one, A. and Gomella, L.G. (2006) Molecular genetics of bladder cancer: Targets for diagnosis and therapy. Journal of Experimental and Clinical Cancer Research, 25(2), 145-160.
[19]	Hasui, Y., Osada, Y., K?tada, S. and Nishi, S. (1994) Significance of invasion to the muscularis mucosae on the progression of superficial bladder cancer. Urology, 43(6), 782-786.
[20]	Yeh, C.W., Huang, S.S., Lee, R.P. and Yung, B.Y. (2006) Ras-Dependent Recruitment of c-myc for Transcriptional Activation of Nucleophosmin/B23 in Highly Malignant U1 Bladder Cancer Cells. Molecular Pharmacology, 70(4), 1443-1453.
[21]	Fontana, D., Bell?na, M., Gubetta, L., Fasol?s, G., Rolle, L., et al. (1992) Monoclonal antibody Ki-67 in the study of proliferative activity of bladder carcinoma. The Journal of Urology, 148(4), 1149-1151.
[22]	Helpap, B. and Kollerman, J. (2000) Assessment of basal cell status and proliferative patterns in flat and papillary urothelial lesions: A contribution to the new WHO classification of urothelial tumors of the urinary bladder. Human Pathology, 31(6), 745-750.
[23]	Koj?ma, K., Murakam?, Y., Kanayama, H. and Kagawa. (1997) Prognostic value of Ki-67 antigen and p53 protein in urinary bladder cancer: Immunohistochemical analysis of radical cyctectomy specimens. British Journal of Urology, 79(3), 367-372.
[24]	Kim, Y.K. and Kim, W.J. (2009) Epigenetic markers as promising prognosticators for bladder cancer. International Journal of Urology, 16(1), 17-22.
[25]	Kim, W.J. and Bae, S.C. (2008) Molecular biomarkers in urothelial bladder cancer. Cancer Science, 99(4), 646- 652.
[26]	Zaharieva, B., Simon, R., Ruiz, C., Oeggerli, M., Mihatsch, M.J., Gasser, T., Sauter, G. and Toncheva, D. (2005) High-throughput tissue microarray analysis of CMYC amplificationin urinary bladder cancer. International Journal of Cancer, 117(6), 952-956.
[27]	Mahdy, E., Pan, Y., Wang, N., Malmstr?m, P.U., Ekman, P. and Bergerheim, U. (2001) Chromosome 8 numerical aberration and C-MYC copy number gain in bladder cancer are linked to stage and grade. Anticancer Research, 21(5), 3167-3173.
[28]	Schmitz-Dr?ger, B.J., Schulz, W.A., Jürgens, B., Gerharz, C.D., van Roeyen, C.R., Bültel, H., Ebert, T. and Ackermann, R. (1997) C-myc in bladder cancer. Clinical findings and analysis of mechanism. Urological Research, 25(1), 45-49.