The present study successfully constructed a genomic classifier for identifying patients with high-risk sPRCC2 using transcriptomic data from multiple cohorts. The high-risk group had a significantly worse prognosis than the low-risk group concerning both OS and DFS. In addition, the high-risk group featured a higher tumor stage, a lymph node stage, a higher frequency of new neoplasm events, lower hemoglobin levels, and a relative higher genomic alteration frequency. The GSEA results indicated that compared with the findings in the low-risk group, gene expression in the high-risk group was significantly enriched in the mTORC1 signaling pathway, which may shed light on the use of mTOR inhibitors. In the external validation, TPX2 expression was used to simulate the classifier according to the logistic regression results, and it could fully match the clusters. This method for simplifying the classifier may be not strictly rigorous, but it also revealed its strong ability to predict OS and PFS in the FUSCC cohort. The stronger efficacy effect of everolimus in the high-risk sPRCC2 group, although not statistically significant, exceeded our expectation.
Previous studies demonstrated that PRCC2 represents a heterogeneous group of lesions that can be divided into various subtypes according to genetic and molecular patterns, and these patterns reflect differences in the clinical course and prognosis of the disease. In a previous study[30], comprehensive genomic profiling was performed to sequence 315 genes, and the commonly altered genes in PRCC2 were CDKN2A/B (18%), TERT (18%), NF2 (13%), and FH (13%). Yang et al.[31] identified two highly distinct molecular PRCC subclasses via morphologic correlation, and they found that G1-S and G2-M checkpoint genes were dysregulated in class 1 and class 2 tumors. A similar pattern was observed in this research. We found that gene expression in high-risk sPRCC2 was enriched in the G2M checkpoint pathway (Fig. 5I), which suggests that the G2M checkpoint plays a key role in the malignant phenotype of sPRCC2. In 2016, the TCGA research network[6] revealed that PRCC2 can be further classified into three individual subgroups based on molecular differences associated with patient survival. In this research, we compared the previously reported classifier with that developed in this study. The predictive accuracy of the two classifiers for OS was similar (Figure S1).
Our results demonstrated that high-risk sPRCC2 was significantly correlated with a higher tumor stage, a higher lymph node stage, and worse OS. Because the treatment of advanced PRCC2 remains difficult, it is of great importance to identify potential targets suppressing PRCC2 growth. As mentioned in a previous study[6], the classification of PRCC may have a significant impact on clinical and therapeutic management and clinical trial design. Mutation of NF2 (the Hippo pathway tumor suppressor) was observed in a number of PRCCs, and this pathway has been targeted in other cancers[32]. The NRF2–ARE pathway was upregulated in both hereditary PRCC and sPRCC2. Currently, researchers are interested in the NRF2–ARE pathway, and novel strategies targeting this pathway have recently been developed[33, 34]. In this study, we found that high-risk sPRCCC2 exhibited excellent mTORC1 signaling pathway activity, which suggests the potential accurate use of mTOR inhibitors. Everolimus, an oral mammalian mTOR inhibitor, has antitumor activity in multiple cancer types[35], and previous research demonstrated that everolimus has some clinical benefit in patients with metastatic PRCC[36, 37]. In our retrospective analysis of the FUSCC cohort, everolimus exhibited a stronger drug effect against high-risk sPRCC2 than against low-risk sPRCC2, and everolimus had greater activity in the high-risk group than sunitinib. This result conferred that the genomic classifier can also guide the accurate use of everolimus in sPRCC2.
This study had several limitations. The nature of retrospective research limits the clinical value of this work. Further validation in multicenter or prospective studies is needed to verify the findings. However, it is difficult to conduct randomized controlled trials in sPRCC2 because of its rarity. There is also an urgent need for in vitro and in vivo experiments to explore the underlying mechanisms behind the genomic classifier.