To construct a robust genomic classi er 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 classi er 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 classi er. Retrospective analysis was used to compare drug e cacy between the groups. Highrisk 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 signi cantly higher in high-risk sPRCC2.Gene set enrichment analysis revealed signi cant 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 signi cantly correlated with worse overall and progression-free survival. Retrospective analysis indicated that mTOR inhibitor (everolimus) had greater e cacy in the high-risk group than in the low-risk group (overall response rate: 28.6% vs. 16.7%) and that everolimus had greater e cacy than sunitinib in the high-risk group (overall response rate: 28.6% vs. 20%). This study successfully constructed a genomic classi er for identifying high-risk sPRCC2. mTOR inhibitors may have good e cacy in patients with high-risk sPRCC2.Fudan University Shanghai Cancer Center GEO Gene Expression Omnibus GSEA gene set enrichment analysis Declarations Acknowledgements: We thank the TCGA databases and GEO (ID: GSE26574, GSE48352) for providing PRCC gene expression pro les. Consent for publication Not applicableAuthor contributions: The work presented here was carried out in collaboration among all authors. YDW, ZHL and QYY de ned the theme of the study and discussed analysis, interpretation and presentation. TX, XWH and Aihetaimujiang drafted the manuscript, analyzed the data, developed the algorithm, and explained the results. WY, LWJ, WHK and WFN, participated in the collection of relevant data and helped draft the manuscript. ZY and CDL helped to perform the statistical analysis. SGH helped revise the manuscript and provided guiding suggestions. All the authors read and approved the nal manuscript.
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