title: Focal amplifications are associated with high grade and recurrences in stage Ta bladder carcinoma.
abstract: Urinary bladder cancer is a heterogeneous disease with tumors ranging from papillary noninvasive (stage Ta) to solid muscle infiltrating tumors (stage T2+). The risk of progression and death for the most frequent diagnosed type, Ta, is low, but the high incidence of recurrences has a significant effect on the patients' quality of life and poses substantial costs for health care systems. Consequently, the purpose of this study was to search for predictive factors of recurrence on the basis of genetic profiling. A clinically well characterized cohort of Ta bladder carcinomas, selected by the presence or absence of recurrences, was evaluated by an integrated analysis of DNA copy number changes and gene expression (clone-based 32K, respectively, U133Plus2.0 arrays). Only a few chromosomal aberrations have previously been defined in superficial bladder cancer. Surprisingly, the profiling of Ta tumors with a high-resolution array showed that DNA copy alterations are relatively common in this tumor type. Furthermore, we observed an overrepresentation of focal amplifications within high-grade and recurrent cases. Known (FGFR3, CCND1, MYC, MDM2) and novel candidate genes were identified within the loci. For example, MYBL2, a nuclear transcription factor involved in cell-cycle progression; YWHAB, an antiapoptotic protein; and SDC4, an important component of focal adhesions represent interesting candidates detected within two amplicons on chromosome 20, for which DNA amplification correlated with transcript up-regulation. The observed overrepresentation of amplicons within high-grade and recurrent cases may be clinically useful for the identification of patients who will benefit from a more aggressive therapy.
authors.affiliation: Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, SE-75185 Uppsala, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Nord
authors.forename: Ulrika
authors.initials: U
authors.lastname: Segersten
authors.forename: Johanna
authors.initials: J
authors.lastname: Sandgren
authors.forename: Kenneth
authors.initials: K
authors.lastname: Wester
authors.forename: Christer
authors.initials: C
authors.lastname: Busch
authors.forename: Uwe
authors.initials: U
authors.lastname: Menzel
authors.forename: Jan
authors.initials: J
authors.lastname: Komorowski
authors.forename: Jan P
authors.initials: JP
authors.lastname: Dumanski
authors.forename: Per-Uno
authors.initials: PU
authors.lastname: Malmström
authors.forename: Teresita
authors.initials: T
authors.lastname: Díaz de Ståhl
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization; D019938:Cyclin D1 / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics; D053671:Syndecan-4 / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D001743:Urinary Bladder / Q000378:metabolism* / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D048948:14-3-3 Proteins; C530104:CCND1 protein, human; D018797:Cell Cycle Proteins; C064352:MYBL2 protein, human; D016271:Proto-Oncogene Proteins c-myc; C508304:SDC4 protein, human; D053671:Syndecan-4; D015534:Trans-Activators; C482982:YWHAB protein, human; D019938:Cyclin D1; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3