Patterns of Chromosomal Imbalances in Advanced Urinary Bladder Cancer Detected by Comparative Genomic Hybridization

Abstract

To identify genetic changes linked to bladder cancer progression we analyzed 90 invasive transitional cell carcinomas (37 pT1 and 53 pT2-4) by comparative genomic hybridization. The most frequent alterations included 1q؉ (37%) , 5p؉ (24%) , 6q؊ (19%) , 8p؊ (29%) , 8q؉ (37%) , 9p؊ (31%) , 9q؊ (23%) , 11p؊ (24%) , 11q؊ (22%) , 17q؉ (29%) , and 20q؉ (28%). Interestingly , there were three groups of alterations that frequently occurred together (9p؊ and 11q13؉/ 20q؉ and 11q13؉ or 17q؉/1q؉ and 3p؉ or 11q؊). These loci might carry genes that interact with each other in specific molecular pathways. There were remarkable genetic similarities between minimally and deeply invasive tumors of different histological grades , including a similar number of aberrations per tumor and an equal frequency of most individual alterations. However , deletions of 5q , 6q , and 15q and gains of 5p , 7p , and Xq were significantly more frequent in pT2-4 than in pT1 carcinomas. These loci may harbor genes that are important for bladder cancer progression. (Am J Pathol 1998, 153:1615-1621) Urinary bladder cancer is the fifth most common malignancy in men in Western societies. The majority of bladder neoplasms are noninvasive (stage pTa). Only approximately 30 to 40% of tumors show invasion at the time of initial diagnosis. Invasion depth is of utmost clinical importance. Tumors having invasion limited to the lamina propria (stage pT1) can be cured by transurethral resection and intravesical therapy in most instances. Prognosis is clearly worse if cancer cells reach the muscular bladder wall (stages pT2 and greater). Approximately 50% of these patients die from their cancer despite aggressive surgery.It appears likely that progression from minimally invasive to deeply invasive cancer goes along with the acquisition of genomic alterations increasing the malignant potential of cancer cells. Previous studies investigating specific alterations have suggested that at least a few molecular changes are more frequent in pT2-4 than in pT1 carcinomas, including epidermal growth factor receptor (EGFR) overexpression and loss of heterozygosity (LOH) at 3p.1,2 A systematic genome-wide screening for differences between the stages pT1 and pT2-4 has not been performed. Previous studies attempting a comprehensive analysis of the entire genome by either allelotype studies or comparative genomic hybridization (CGH) have focused on early-stage tumors 3,4 or analyzed only a small number of tumors. 5,6 In this study, we analyzed a series of 90 invasive urinary bladder carcinomas by CGH to search for genomic alterations that are associated with tumor progression. CGH allows detection of all relative DNA sequence copy number gains and losses of a tumor in one examination. 7 The results implicate several genomic alterations that may play a role in bladder cancer progression.

TRIO Amplification and Abundant mRNA Expression Is Associated with Invasive Tumor Growth and Rapid Tumor Cell Proliferation in Urinary Bladder Cancer

“…In previous CGH studies 5p amplification was found to be one of the few alterations occurring more frequently in muscle invasive tumors (stage pT2 and higher) than in early invasive cancers (stage pT1). 5 Our hypothesis of a role of 5p amplification for bladder cancer progression was further corroborated by the results of a second CGH study finding a significant association between 5p amplifications and an increased risk for tumor progression in a series of pT1 carcinomas. 6 Because amplifications often cover large areas of 5p in bladder cancer, it is difficult to narrow down the region of amplification using positional cloning approaches.…”

“…This result is consistent with a previous CGH study in which 5p aberrations occurred significantly more frequent in pT2-4 tumors than in pT1 tumors. 5 The rate of muscle-invasive tumors with TRIO amplifications was somewhat higher than that of pT2-4 tumors analyzed with CGH. It is likely that in some cases regional amplifications were interpreted as gain rather than amplification because of technical or DNA quality reasons.…”

“…However, the portion of pT2-4 tumors with TRIO copy numbers Ն3 was 30%, which is similar to that observed by CGH analysis. 5,34 It is of note that 5p gains detected by CGH were associated with high risk of progression in early invasive (pT1) bladder cancer in one study. 6 This finding was interpreted with caution because only 5 of 54 pT1 tumors analyzed demonstrated 5p gains.…”

“…Based on our CGH studies, one of the most common sites of amplification is in the 5p15-p14 region. 5 In an attempt to find oncogene candidates among known genes allocated in this chromosomal area, we became interested in TRIO located at 5p15.2. 7 The TRIO protein contains a serine/threonine kinase domain and two guanine nucleotide exchange factor domains for the family of Rho-like GTPases, specific for Rac1 and RhoA.…”

Defining a 0.5-Mb Region of Genomic Gain on Chromosome 6p22 in Bladder Cancer by Quantitative-Multiplex Polymerase Chain Reaction

“…These studies have illustrated the genomic complexity of bladder cancer and have identified recurrent regions of DNA copy number increase or high level amplification on several chromosomes including; 1q, 5p, 6p, 8q, 10p, 12q, 17q, and 20q. [3][4][5][6][7][8][9] These genomic regions are thought to contain oncogenes that may be important in tumor progression.…”