203P Characterization of renal cell carcinoma (RCC) with VHL mutation

VHL is one of the most commonly mutated oncogene in RCC. However, different co-mutated genes and VHL mutation types are associated with different prognoses and treatments. A more comprehensive understanding of the genomic landscape relative to different VHL variant subsets will help guide therapeutic development. Molecular profiles of 322 RCC samples were obtained using next-generation sequencing of 808 genes (Acornmed Corporation) and classified based on the presence and types of VHL variant. Incidence of VHL mutations was noted across the cohort. Co-occurring genomic alterations and tumor mutational burden (TMB) were analyzed by VHL mutation type. Across the entire cohort, 163 VHL mutations were detected among 154 patients(47.8%). Frameshift mutations were the most prevalent mutation type, accounting for the 42.9%(70/163), followed by missense, nonsense, splicing mutation, copy number loss(42.4%(69/163), 9.2%(15/163), 4.3%(7/163) and 1.2%(2/163) respectively). These mutations were classified into structural variant(58.4%) and non-structural variant(41.6%) based on the effects of variants on protein structure. PBRM1, SETD2, BAP1, KDM5C were commonly co-occurring with VHL(all p<0.05). SETD2 and KDM5C mutations were more common in VHL-nosv RCC, followed by VHL-sv and the VHL-wt. BAP1 has a similar mutation frequency in cases of VHL-sv and VHL-nosv, while VHL-wt had a lower frequency. PBRM1 was mutated in 10.1% of VHL wild type RCC but more frequently noted in both VHL subtype, with the higher rate in VHL-sv (43.3%) and lower in VHL-nosv(29.7%). TMB-H was defined by >12.8 mutations/Mb(upper quartile of the cohort). TMB-H varied across the different VHL mutation subset, most common in VHL-sv (31.1%) and least common in VHL wild type(VHL-wt) (22.2%). VHL mutations are relatively common in Renal cell Carcinoma and VHL structural variant is the most common type. The different VHL mutation has different co-occurring mutations and a different genomic landscape. VHL-sv was associated with the highest rate of TMB and PBRM1 frequency. These different clinical correlates in terms of therapeutic interventions need to be investigated.