PIK3CA gene alterations in bladder cancer: Analysis of correlative series of transurethral resection (TUR)—Correlation with grade histology and tumor size.

Abstract

4584 Background: PI3K pathway involvement in bladder cancer is well documented and activating mutations of the gene have been identified, particularly in tumors of low grade and stage. We have analyzed hot spot mutations and copy number in PIK3CA gene as well as mRNA expression levels in tumor tissue of pts with urothelial cell carcinoma (UCC). Methods: 90 pts were analyzed. In 85 pts, fresh tissue from tumor and adjacent normal tissue was collected. All pts signed an informed consent and basic demoghrapics data were collected. Histology confirmation of UCC was required. PIK3CA alterations were analyzed by quantative-PCR. Results: Patient«s characteristics were: median age 73 years, Ta 45.5%, T1 41.1%, T2 12.2%; high-grade histology 43.4%, low-grade 51,1%, PULMP 4,4%. With a median follow-up of 10.0 months, 21% tumor recurrences were observed. 13% normal tissue and 51,8% tumor samples harbored alterations in PIK3CA gene, including alterations affecting the helical domain (mutations 65%, amplifications 60%, both 21%). According to T stage the distribution was: 10/36 Ta, 26/35 T1 y 6/10 T2. (p<0.05). When analyzing factors related to tumor recurrence, it was found that PIK3CA gene mutations in E542 or E545 had a lower recurrence risk (p-value ²0.045). Differential expression analysis (genome-wide transcriptome analysis/microarray) showed that tumors bearing altered PIK3CA gene are more similar to non-tumoral samples comparing with tumors bearing wtPIK3CA gene. Moreover, overexpressed genes in mutant samples are mainly involved in G-protein and Wnt signaling, whereas underexpressed genes are involved in cell morphogenesis and cell polarity. Conclusions: We observed that PIK3CA gene alterations is an early carcinogenesis event in UCC pts, and more frequently found in larger tumor stages. These data support that PIK3CA status may constitute a good prognostic tool, as well as a therapeutic target in stratified groups for bladder cancer.