Abstract 1477P
Background
VHL as a tumor suppressor gene is the most common mutant gene in clear cell renal cell carcinoma (ccRCC), and inactivating alterations of VHL gene lead to HIF-2α accumulation, which induces the tumor progression. Recently the inhibitor of HIF-2α, Belzutifan was approved by FDA for patients with solid tumors harboring germline VHL mutations. However, the prevalence of somatic VHL variants in Chinese solid tumors remained unclear.
Methods
VHL alteration frequencies in Chinese patients with solid cancers were analyzed from the dataset of 3DMed Inc., including copy number variations and single nucleotide variations (SNV). Among SNV, only the pathogenic mutations and likely pathogenic mutations in clinical significance were rolled into our analysis. The correlations between putative VHL copy number status from GISTIC and HIF-2a (EPAS1 gene), CTLA4, CD4, CD8A mRNA expression in ccRCC were analyzed using the public datasets accessible from cBioPortal.
Results
In our dataset, more than 100,000 patients were included in the analysis. VHL alterations were most prevalent in ccRCC (66.7%, 234/351), mostly belonging to SNV (64.7%, 227/351). And it was followed by synovial sarcoma (14.3%, 7/49) and small cell lung cancer (SCLC, 10.7%, 53/494). Unlike in ccRCC, all VHL alterations in those two tumors belonged to the type of copy number loss. In the datasets available from cBioportal, deep or shallow deletion of VHL copy number alterations was correlated with lower VHL expression and higher EPAS1 expression compared to diploid, which indicated the potential of belzutifan as a target drug for ccRCC patients haboring somatic VHL mutation. In addition, higher levels of CTLA4, CD4 and CD8A expression in patients with deep or shallow deletion of VHL CNA suggested that inactivation of VHL protein mediated tumor escape by increasing CTLA-4+ T cell infiltration.
Conclusions
Besides of the high prevalence in ccRCC, somatic VHL variants accounted for 14.3% of synovial sarcoma and 10.7% SCLC patients, who may benefit from belzutifan. Furthermore, the higher CTLA-4 expression in the group with inactivation of VHL protein suggested the immune checkpoint inhibitor targeting CTLA-4 or their combination with belzutifan may be a promising option for ccRCC patients with VHL mutation.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.