ICCFGG 2022
#48 Whole exome sequencing analysis of canine urothelial carcinomas without canonical BRAF V595E mutation Rachael Thomas1,2 , Claire A. Wiley1, Emma L. Droste1, James Robertson3, Brant A. Inman4,5, and Matthew Breen1,2,5,6 rthomas3@ncsu.edu 1Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA, 2Comparative Medicine Institute, North Carolina State University, Raleigh, NC, USA, 3Office of Research (Biostatistics), College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA, 4Department of Surgery, School of Medicine, Duke University, Durham, NC, 5Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA, 6Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, USA Molecular profiling studies have shown that 85% of canine urothelial carcinomas (UC) harbor an activating BRAF V595E mutation, which is orthologous to the V600E variant found in several human cancer subtypes. In dogs, this mutation provides both a powerful diagnostic marker and a potential therapeutic target; however, due to their relative infrequency, the remaining 15% of cases remain understudied at the molecular level. We performed whole exome sequencing analysis of 28 canine urine sediments exhibiting the characteristic DNA copy number signatures of canine UC, in which the BRAF V595E mutation was undetected (V595E-UD specimens). Among these, 7/28 cases (25%) harbored mutations within the same gene, and a further 6/28 (21%) exhibited variants in a second gene within the same pathway. These mutations clustered in hotspot regions, and were mutually exclusive. Notably, orthologous variants occur in several human cancer subtypes and confer structural changes to the protein product that are predictive of response to certain inhibitor therapies. We developed a multiplexed assay for screening additional clinical specimens, which demonstrated that these variants are evident in independent V595E-UD cohorts, as well as several other canine cancer subtypes. DNA damage response and repair genes, and chromatin modifiers were also recurrently mutated in V595E-UD specimens, as were genes that are positive predictors of immunotherapy response in human cancers. Our findings suggest alternative mechanisms for UC pathogenesis that may have significant implications for selecting first-line treatment for canine UC.
92
Made with FlippingBook - Online magazine maker