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 T21). 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.Urinary bladder cancer is a common malignant disease that ranks fourth among all cancers in Europe with 91,000 new cases and 37,000 deaths annually. 1 The prevalence is 3 to 8 times higher than the incidence, making bladder cancer one of the most prevalent neoplasms, and hence, a major burden for all health care systems. The biology of this disease is heterogeneous with tumors ranging from papillary noninvasive (stage Ta) to solid muscle infiltrating high-grade tumors (stage T2þ). The histologic grade usually parallels the stage, and thus, low-grade is common in lower, whereas high-grade predominates in higher stages. The most frequent form of all newly diagnosed cancers is of the stage Ta category, usually of low grade, which constitute more than half of all newly diagnosed cases. These tumors are considered to evolve from urothelial hyperplasia and are often multifocal. After initial transurethral resection (TUR), approximately 70% recur in the bladder, which makes this tumor type responsible for the high prevalence rate. The risk of progression and death is small, but the frequency of recurrences has a significant effect on the patients' quality of life and poses a substantial cost for the health care systems. Consequently, an attempt to prevent recurrences is frequently made by intravesical instillations either by...

Gene expression profile and enrichment pathways in different stages of bladder cancer

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Advanced urothelial carcinoma: next-generation sequencing reveals diverse genomic alterations and targets of therapy

“…Although the expression of cyclin D1, detected by IHC, has been reported in approximately 80% of UC, 53,54 CCND1 amplification has been reported in approximately 10% of UC of the bladder primarily in high-grade tumors. 55,56 There are no approved therapies that directly target cyclin D1, which is the protein product of CCND1; however, CCND1 amplification might predict sensitivity to inhibitors of Cdk4 and Cdk6, which are currently being tested in clinical trials. MDM2, a regulator of TP53, has been reported as being amplified in up to 10% of UCs.…”

Prognostic significance of the co-overexpression of fibroblast growth factor receptors 1, 2 and 4 in gastric cancer

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