ORLANDO, FL USA (UroToday.com) - Dr. Seth Lerner from Baylor College of Medicine presented his group’s findings from The Cancer Genome Atlas (TCGA) project. TCGA projects are the comprehensive description and integrated analysis of somatic mutations and expression profiling including mRNA, protein, and methylation for every individual tumor. As part of the TCGA bladder project, DNA from 131 muscle-invasive urothelial bladder cancer tumors and corresponding normal samples were analyzed. It was reported that with every tumor, on average, 302 exonic mutations, 204 segmental alterations in DNA copy, and 22 genomic alterations were seen. Moreover, 32 recurrent significantly mutated genes were identified which were involved in bladder cancer pathogenesis.
Moreover, roughly 69% of tumors had at least 1 “significantly mutated gene” or SMG, suggesting a strategy for personalized targeted therapy in most of the patients with invasive, high-grade bladder cancer. Several altered genes were identified as potential therapeutic targets for patients with advanced urothelial carcinoma (UC) (e.g., PIK3CA, ERBB2, FGFR3, TSC1, ERBB3). By single-nucleotide polymorphism arrays, multiple areas of somatic copy number alterations (SCNAs) were identified, with CDKN2A deletion being the most common one (47%). Although the role of viral infection in the pathogenesis of UC remains unclear, viral DNA (cytomegalovirus, human herpes virus 6B, human papilloma virus-16, or BK polyomavirus), was identified in 6% and viral transcripts were identified in 4% (CMV, BK polyoma virus, HPV16). Furthermore, integrated analysis revealed that multiple pathways are recurrently altered in UC, including cell cycle regulation (93%), kinase and PI3-K signaling (72%), and epigenetic regulators (such as: histone modifying genes (89%); SWI/SNF nucleosome remodeling complex ( 64%)).
As a result of these interesting findings, the scientists involved with this project concluded that bladder cancer is one of the most highly mutated tumor types, similar to lung cancer, breast cancer, and melanoma. These findings suggest that perhaps already FDA-approved drugs that are effective in these other tumor types could potentially be effective in urothelial cancers that share the same molecular phenotype(s). The major take-home point from TCGA project is that the majority of patients with MIBC have some sorts of actionable mutations and that epigenetic regulatory genes are frequently altered in this type of bladder cancer, suggesting that there may be a different paradigm for therapeutic intervention. More basic science and clinical research, as well as assistance from biotech and pharmaceutical companies, are needed to identify drugs that target these alterations.
The amount of work that TCGA group has put into this project is tremendous, and the cooperation by the team of almost 300 authors is a monumental achievement. Their work should be highly regarded for the many novel findings described.
Presented by Seth P. Lerner, MD at the American Urological Association (AUA) Annual Meeting - May 16 - 21, 2014 - Orlando, Florida USA
Baylor College of Medicine, Houston, TX USA
Written by Reza Mehrazin, MD, medical writer for UroToday.com