High-throughput tissue microarray analysis of 11q13 gene amplification (CCND1, FGF3, FGF4, EMS1) in urinary bladder cancer

• Published in: The Journal of pathology 2003-12, Vol.201 (4), p.603-608
• Main Authors: Zaharieva, Boriana M, Simon, Ronald, Diener, Pierre-Andre, Ackermann, Daniel, Maurer, Robert, Alund, Göran, Knönagel, Hartmut, Rist, Marcus, Wilber, Kim, Hering, Franz, Schönenberger, Andreas, Flury, Renata, Jäger, Peter, Fehr, Jean Luc, Mihatsch, Michael J, Gasser, Thomas, Sauter, Guido, Toncheva, Draga I
• Format: Article
• Language: English
• Subjects: 11q13 amplicon; Adenocarcinoma - genetics; Adult; Aged; Aged, 80 and over; Biological and medical sciences; bladder cancer; Carcinoma, Small Cell - genetics; Carcinoma, Squamous Cell - genetics; Carcinoma, Transitional Cell - genetics; Chromosomes, Human, Pair 11 - genetics; Cortactin; cyclin D1; Cyclin D1 - genetics; DNA, Neoplasm - analysis; Female; Fibroblast Growth Factor 3; Fibroblast Growth Factor 4; Fibroblast Growth Factors - genetics; fluorescence in situ hybridization (FISH); Gene Amplification - genetics; Genes, bcl-1 - genetics; Humans; In Situ Hybridization, Fluorescence - methods; Male; Medical sciences; Microfilament Proteins - genetics; Middle Aged; Neoplasm Staging; Nephrology. Urinary tract diseases; Oligonucleotide Array Sequence Analysis - methods; Oncogenes - genetics; Phenotype; Prognosis; Proto-Oncogene Proteins - genetics; tissue microchips; Tumors of the urinary system; Urinary Bladder Neoplasms - genetics; Urinary tract. Prostate gland
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.1481

Gene amplification is a common mechanism for oncogene overexpression. High‐level amplifications at 11q13 have been repeatedly found in bladder cancer by comparative genomic hybridization (CGH) and other techniques. Putitative candidate oncogenes located in this region are CCND1 (PRAD1, bcl‐1), EMS1, FGF3 (Int‐2), and FGF4 (hst1, hstf1). To evaluate the involvement of these genes in bladder cancer, a tissue microarray (TMA) containing 2317 samples was screened by fluorescence in situ hybridization (FISH). The frequency of gains and amplifications of all genes increased significantly from stage pTa to pT1–4 and from low to high grade. In addition, amplification was associated with patient survival and progression of pT1 tumours. Among 123 tumours with amplifications, 68.3% showed amplification of all four genes; 19.5% amplification of CCND1, FGF4, and FGF3; and 0.8% co‐amplification of FGF4, FGF3, and EMS1. Amplification of CCND1 alone was found in 9% of the tumours, while EMS1 alone was amplified in 1.6% and FGF4 in 0.8%. Overall, the amplification frequency decreased with increasing genomic distance from CCND1, suggesting that, among the genes examined, CCND1 is the major target gene in the 11q13 amplicon in bladder cancer. Copyright © 2003 John Wiley & Sons, Ltd.