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

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.

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 VHL ^Trunc and VHL ^Miss. The association of VHL status with clinical outcomes, genomic, oncogenic and immunologic characteristics was further depicted.

VHL ^Miss ccRCC was associated with reduced survival in the localized ZSHS and The Cancer Genome Atlas cohorts. Clinical benefit from immunotherapy was observed in VHL ^Miss patients in all immunotherapy cohorts. VHL ^Miss 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, VHL ^Miss ccRCC featured an inflamed microenvironment with enriched tertiary lymphoid structures.

VHL ^Miss mutations delineate an aggressive ccRCC subtype with distinct clinical outcomes, likely attributed to its specific oncogenic, morphologic and immunologic features.