BRIEF COMMUNICATION Overexpression of Genes on 16q Associated with Cisplatin Resistance ofTesticular Germ Cell Tumor Cell Lines Charlotte Wilson, 1y Jinshu Yang, 1y Jon C. Strefford, 1 Brenda Summersgill, 2 Bryan D. Young, 1 Janet Shipley, 2 Tim Oliver, 1 and Yong-Jie Lu 1 * 1 Department of Medical Oncology,Barts and London School of Medicine and Dentistry,Queen Mary,University of London, Charterhouse Square,London,United Kingdom 2 Molecular Cytogenetics, Institute of Cancer Research, Sutton, Surrey,United Kingdom Testicular germ-cell tumors (TGCTs) showexquisite sensitivity to cisplatin-based chemotherapy, and therefore this is consid- ered a good model system for studying the mechanism of chemotherapy resistance. Although the genetic alterations related to TGCT have been well studied, little is known about the genetic basis of chemotherapy resistance, which occurs in a small proportion of TGCTs. In this study, we investigated genomic and expression differences between three cisplatin-sensitive and their paired cisplatin-resistant lines using combined whole-genome screen approaches. Comparative genomic hybridization (CGH) analysis on chromosomes revealed genetic differences between the resistant and parent cell lines in each pair, but did not show any consistent chromosome changes in all three lines. Microarray CGH analysis generated some additional informa- tion of DNA copy number gains and losses including some important oncogenes, tumor-suppressor genes, and drug-resist- ance-related genes. However, no consistent genomic region changes were found in the three cell lines. Interestingly, when comparative expressed sequence hybridization, a technique for gene expression profiling along chromosomes, was applied, we discovered a consistently overexpressed chromosomal region in all three resistant lines compared with their parent lines. The minimum overlapping chromosomal region is at 16q22–23. Further definition of genes in this chromosomal region will aid our understanding of the mechanism of cisplatin resistance and may offer novel therapeutic targets. ' 2005 Wiley-Liss, Inc. Testicular germ cell tumor (TGCT) is the most common tumor in young men (Bosl and Motzer, 1997). Its exquisite sensitivity to cisplatin-based chemotherapy distinguishes this tumor from others (Chaganti and Houldsworth, 2000; Masters and Koberle, 2003). More than 80% of TGCTs with metastatic disease are curable using the cisplatin- based chemotherapy regime of cisplatin, bleomy- cin, and etoposide (Bosl and Motzer, 1997). The studies to understand the genetic changes gener- ally linked to TGCT development have been pro- ductive. Characteristic gain of 12p material, which occurs in almost all TGCTs, has been established as a diagnostic marker for TGCT (Bosl and Chaganti, 1994; Murty and Chaganti, 1998; Oliver, 2000). CCND2, which is overexpressed in this chro- mosomal region, has a potential role in TGCT development (Houldsworth et al., 1997; Heiden- reich et al., 2000; Rodriguez et al., 2003), and other genes from this region such as KRAS may play important roles, also (Mostert et al., 1998; Roelofs et al., 2000; Rodriguez et al., 2003). Mutation of KIT also is involved in TGCT transforma- tion (Devouassoux-Shisheboran et al., 2003; von Eyben, 2004). Unlike other tumors, TP53 is rarely found to be mutated, and its function is up- regulated (Chaganti and Houldsworth, 2000; Oliver, 2000; Kersemaekers et al., 2002; Mayer et al., 2003a, 2003b; Spierings et al., 2003). BCL2,a gene frequently up-regulated in human cancers in order to inactivate the apoptosis pathway is usually detected at low levels in TGCT (Oliver, 2000; Mayer et al., 2003b; Spierings et al., 2003). The elevated function of wild-type TP53 and the low- level expression of BCL2 partly explain the exqui- site chemosensitivity of TGCT. Misfunction of excision DNA repair and alterations of other genes also have been found to be related to the unique response to cisplatin (Burger et al., 1999; Meijer et al., 2000; Oliver, 2000; Masters and Koberle, 2003; Mayer et al., 2003a, 2003b). However, few of the genetic changes found in TGCT have been linked to tumor progression, and *Correspondence to: Yong-Jie Lu, Department of Medical Oncology, Barts and London School of Medicine and Dentistry, Queen Mary, University of London, Charterhouse Square, London, EC1M 6BQ. E-mail: yong.lu@cancer.org.uk Supported by: Orchid Cancer Appeal and Cancer Research UK. y Those authors contributed equally. Received 24 August 2004; Accepted 23 December 2004 DOI 10.1002/gcc.20173 Published online 10 March 2005 in Wiley InterScience (www.interscience.wiley.com). ' 2005 Wiley-Liss, Inc. GENES, CHROMOSOMES & CANCER 43:211–216 (2005)