SAN FRANCISCO, CA USA (UroToday.com) - Dr. Jonathan E. Rosenberg, on behalf of the Cancer Genome Atlas Bladder Cancer Working Group, presented an update on TCGA bladder cancer.
He started his presentation by acknowledging that invasive and metastatic urothelial cancer (UC) is a major cause of morbidity and mortality, with few other good therapeutic options beyond cisplatin-based chemotherapy. In order to understand the biology of invasive UC this group analyzed 131 high-grade muscle invasive UC tumors that had not received prior chemotherapy. Each tumor was analyzed in an integrated model and whole-exome sequencing revealed 29 genes that were significantly mutated. Several altered genes were identified as potential therapeutic targets for patients with advanced UC (e.g., PIK3CA, ERBB2, FGFR3, TSC1, ERBB3). By single-nucleotide polymorphism arrays, multiple areas of somatic copy number alterations (SCNAs) were identified, and CDKN2A deletion being the most common one (47%). Although the role of viral infection in the pathogenesis of UC remains undefıned, viral DNA was identified in 6% (cytomegalovirus [CMV], human herpes virus 6B, human papilloma virus 16 [HPV16], BK polyomavirus), and viral transcripts were identified in 4% (CMV, BK polyoma virus, HPV16).
Using mRNA expression analysis of RNA-seq data, 4 tumor clusters were identified. Cluster I known to be enriched with papillary morphology and FGFR3 mutation, and miRNAs that down-regulate FGFR3. Both Cluster I and Cluster II expressed high levels of HER2 (ERBB2) and estrogen receptor beta signaling signature and shared similarities to Luminal A breast cancer. Cluster III was similar to basal-like breast cancers and squamous cell carcinomas of the head and neck and expressed cytokeratins KRT 5 and KRT14. Also some of the Cluster III tumors showed some levels of squamous differentiation on histologic evaluation.
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 (histone modifying genes: 89%; SWI/SNF nucleosome remodeling complex: 64%). Considering that median follow-up is short, no significant clinical associations between molecular alteration and outcomes were identified. At last, the presentation was concluded by acknowledging that drugs targeting epigenetic regulatory pathways (such as bromodomain inhibitors) should be considered for investigation in UC and these data can assist with design of clinical trials in which patients with relevant genomic alterations are assigned to treatment based on tumor-specific alterations.
Highlights of a presentation by Jonathan E. Rosenberg, MD at the 2014 Genitourinary Cancers Symposium - January 30 - February 1, 2014 - San Francisco Marriott Marquis - San Francisco, California USA
Memorial Sloan Kettering Cancer Center, New York, NY USA