Construction and Validation of a Robust Genomic Classifier for High-Risk Sporadic Type 2 Papillary Renal Cell Carcinoma: Support More Accurate Utilization of mTOR inhibitors
To construct a robust genomic classifier for high-risk sporadic type 2 papillary renal cell carcinoma (sPRCC2) and identify potential therapeutic targets. A cohort from The Cancer Genome Atlas and two datasets from Gene Expression Omnibus were examined. Common differentially expressed genes were screened, and the ConsensusClusterPlus package was used to identify potential high-risk molecular subtypes of sPRCC2. Targeting protein for Xklp2 (TPX2) expression was used to simulate the classifier according to the logistic model. Ninety-two samples from Fudan University Shanghai Cancer Center (FUSCC) were obtained, and TPX2 immunostaining was performed to validate the predictive ability of the genomic classifier. Retrospective analysis was used to compare drug efficacy between the groups. High-risk sPRCC2 had worse overall (hazard ratio [HR] = 7.804) and disease-free survival (HR = 8.777) than low-risk sPRCC2, and the tumor and lymph node stages were significantly higher in high-risk sPRCC2. Gene set enrichment analysis revealed significant enrichment of genes in the mammalian target of rapamycin (mTOR) complex 1 signaling pathway in the high-risk group. In the FUSCC cohort, high-risk sPRCC2 (high TPX2 expression) was significantly correlated with worse overall and progression-free survival. Retrospective analysis indicated that mTOR inhibitor (everolimus) had greater efficacy in the high-risk group than in the low-risk group (overall response rate: 28.6% vs. 16.7%) and that everolimus had greater efficacy than sunitinib in the high-risk group (overall response rate: 28.6% vs. 20%). This study successfully constructed a genomic classifier for identifying high-risk sPRCC2. mTOR inhibitors may have good efficacy in patients with high-risk sPRCC2.