VHL missense mutation delineate aggressive clear cell renal cell carcinoma subtype with favorable immunotherapeutic response

Abstract

Background von Hippel-Lindau (VHL) harbors the highest mutational frequency in clear cell renal cell carcinoma (ccRCC). Although VHL mutational subtypes exert diverse impacts on the functionality of the VHL protein, the clinical significance of VHL mutational heterogeneity remains largely obscure.Methods This study included a total of 1331 patients with ccRCC from localized data sets, including our localized Zhongshan Hospital (ZSHS) cohort (n=1270) and Zhongshan immune checkpoint blockade cohort (n=61), as well as 525 patients with ccRCC from two publicly available data sets with matched clinical annotation and multidimensional data. According to the putative biological effect, we subclassified VHL mutation into VHLTrunc and VHLMiss. The association of VHL status with clinical outcomes, genomic, oncogenic and immunologic characteristics was further depicted.Results VHLMiss ccRCC was associated with reduced survival in the localized ZSHS and The Cancer Genome Atlas cohorts. Clinical benefit from immunotherapy was observed in VHLMiss patients in all immunotherapy cohorts. VHLMiss ccRCC exhibited hyper-activated cell cycle and nuclear factor kappa B (NF-κB) instead of canonical hypoxia inducible factor pathways, which might contribute to its proliferative morphology. Meanwhile, VHLMiss ccRCC featured an inflamed microenvironment with enriched tertiary lymphoid structures.Conclusions VHLMiss mutations delineate an aggressive ccRCC subtype with distinct clinical outcomes, likely attributed to its specific oncogenic, morphologic and immunologic features.