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Background  Urothelial carcinoma (UC) is characterized by nonrandom chromosomal aberrations, varying from one or a few changes in early-stage and low-grade tumors, to highly rearranged karyotypes in muscle-invasive lesions. Recent array-CGH analyses have shed further light on the genomic changes underlying the neoplastic development of UC, and have facilitated the molecular delineation amplified and deleted regions to the level of specific candidate genes. In the present investigation we combine detailed genomic information with expression information to identify putative target genes for genomic amplifications.    Methods  We analyzed 38 urothelial carcinomas by whole-genome tiling resolution array-CGH and high density expression profiling to identify putative target genes in common genomic amplifications. When necessary expression profiling was complemented with Q-PCR of individual genes.    Results  Three genomic segments were frequently and exclusively amplified in high grade tumors; 1q23, 6p22 and 8q22, respectively. Detailed mapping of the 1q23 segment showed a heterogeneous amplification pattern and no obvious commonly amplified region. The 6p22 amplicon was defined by a 1.8 Mb core region present in all amplifications, flanked both distally and proximally by segments amplified to a lesser extent. By combining genomic profiles with expression profiles we could show that amplification of  E2F3, CDKAL1 ,  SOX4 , and  MBOAT1  as well as  NUP153, AOF1, FAM8A1  and  DEK  in 6p22 was associated with increased gene expression. Amplification of the 8q22 segment was primarily associated with  YWHAZ (14-3-3-zeta)  and  POLR2K  over expression. The possible importance of the  YWHA  genes in the development of urothelial carcinomas was supported by another recurrent amplicon paralogous to 8q22, in 2p25, where increased copy numbers lead to enhanced expression of  YWHAQ  ( 14-3-3-theta ). Homozygous deletions were identified at 10 different genomic locations, most frequently affecting  CDKN2A/CDKN2B  in 9p21 (32%). Notably, the latter occurred mutually exclusive with 6p22 amplifications.    Conclusion  The presented data indicates 6p22 as a composite amplicon with more than one possible target gene. The data also suggests that amplification of 6p22 and homozygous deletions of 9p21 may have complementary roles. Furthermore, the analysis of paralogous regions that showed genomic amplification indicated altered expression of  YWHA  (14-3-3) genes as important events in the development of UC.

bmc medical genomics

Tiling resolution array CGH and high density expression profiling of urothelial carcinomas delineate genomic amplicons and candidate target genes specific for advanced tumors