COMPARATIVE GENOMIC HYBRIDIZATION STUDY OF INVASIVE TRANSITIONAL CELL CARCINOMAS OF THE URINARY BLADDER OF BULGARIAN PATIENTS
Zaharieva B1, Damianov Ch2, Tabakov V2, Tzingilev B2, Nikolov I1, Georgiev Ch3, Toncheva D1
*Corresponding Author: Toncheva D. Department of Medical Genetics, Medical University Sofia, 2 Zdrave str, 1431 Sofia, Bulgaria Tel/Fax: + 359 2 9520357 email: draga@spnet.net
page: 31

INTRODUCTION

Epidemiology. Bladder cancer is the fifth most common cancer in Western societies while it takes 9th place in Bulgaria with mortality rate 2:1. It is usually developed after 60 years of age and appears to be mostly a result of exogeneous factors although rare cases of familial bladder cancer have been reported [1].

Molecular carcinogenesis in bladder cancer. Studies in experimental systems have shown that interactions of the carcinogenes (arylamines, 4-nitrobyphenils, etc.) with genomic DNA results in mutational activation of oncogenes and inactivation of tumor-suppressor genes. Tumor development is associated with accumulation of genetic changes. Revealing of these genetic changes is important for pointing out those of specific diagnostic and prognostic value.

Comparative genomic hybridization (CGH) is a powerful tool for screening whole tumor genomes for DNA sequence copy number changes [2]. Using only small amount of tumor DNA, this approach allows for whole genome screening for unbalanced genetic material. Main advantage of the CGH technology is the posibility to obtain information on the genetic changes in non-dividing cells (solid tumors, not suitable for cytogenetic analysis). The minimum size of the region affected is 10-20 ?b. In the cases of high level amplification the limit goes to hundreds kb.

CGH in bladder cancer. Comparative studies between non-invasive (pTa) and minimally invasive (pT1) tumors have shown increased genomic instability in pT1 tumors. Loss of chromosome 9 material and gains of chromosome 17 have been frequently detected in pTa tumors but not in invasive tumors [3]. Specific alterations for pT1 stage have been shown to be deletions of 2q, 8p, 11p and gains at 1q, 8q, 3p, 3q, 5p, 6p and 10p, suggesting that theses loci are candidates for carrying genes involved in invasive tumor growth in bladder cancer [4]. In another study individual cytogenetic alterations that have been linked to tumor progression (pT1 tumors) included gains of 3p22-24 and 5p as well as losses of 4p11-15, 5q15-23, 6q22-23, 10q24-26 and 18q12-23 [5]. No specific genetic changes have been found to be overrepresented in metastases compared to their primary tumors [6].

Previous studies by immunochistochemistry and microsatellite analysis have suggested that some molecular changes are more frequent in pT2-4 than in pT1 tumors including epidermal growth factor receptor (EGFR) overexpression and loss of heterozygossity at 3p [7, 8].

A systematic genome screening between pT1 and pT2-4 bladder carcinomas by CGH has been performed only once by Righter et al. [9]. According to their data the most frequent genetic alterations in invasive tumors (pT1-4) included gains at 1q, 5p, 8q, 17q, 20q and losses of 6q, 8p, 9p, 9q, 11p, and 11q. The authors have found remarcable genetic similarities between minimally (pT1) and deeply invasive tumors (pT2-4), but deletions of 5q, 6q and 15q as well as gains at 5p, 7p, and Xq, were significantly more frequent in pT2-4 than in pT1 carcinomas.

The aim of our study was to perform a comparative genomic hybridization study of invasive transitional cell carcinomas of the urinary bladder of Bulgarian patients in order to compare the genomic instability of pT1 and pT2-4 invasive tumors as well as to search for specific chromosomal regions associated with muscle invasion (pT2-4).




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