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

Background

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.

Methods

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.

Results

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%).

Conclusions

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.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

Y. Zhang, T. Yang, W. Wang, H. Wang, F. Lou, S. Cao: Full/Part-time employment: Beijing Acornmed Biotechnology Co., Ltd.