Identification of molecular subtypes based on chromatin regulator and tumor microenvironment infiltration characterization in papillary renal cell carcinoma.

Background: Papillary renal cell carcinoma (pRCC) is the second most common histological type of renal cell carcinoma. The prognosis of local pRCC is better than that of ccRCC, but the situation has changed greatly after pRCC metastasis. Chromatin regulators (CRs) are indispensable in epigenetic regulation, and their abnormal expression in tumors leads to the occurrence and development of tumor. However, the role of CRs in pRCC has not been studied yet.

Materials And Methods: 291 samples were obtained from TCGA-KIPR cohort. Unsupervised clustering analysis was utilized to divide the patients of pRCC into two subtypes. Lasso Cox regression analysis was performed to construct a CRs_score model for predicting OS. The unique characteristics of different molecular subtypes were determined by TME cell infiltration analysis, GO and KEGG analysis and drug sensitivity analysis. We also carried out drug sensitivity experiments in vitro to verify the effect of signature genes on drug sensitivity to sunitinib.

Results: We described the transcriptional and genetic alteration of 19 prognosis-related CRs genes in 291 cases of TCGA-KIRP cohort. We identified two distinct molecular subtypes, which have significant differences in prognosis, clinicopathological features and tumor immune microenvironment (TME). Then, four signature genes were selected by lasso regression analysis to construct a CRs_score for predicting OS, and its predictive ability for patients with pRCC was verified. A nomogram was established to improve the clinical applicability of CRs_score. We found that there was a significant difference in the proportion of immune cell infiltration between high- and low-CRs_score. In addition, CRs_score was significantly correlated with chemosensitivity. Finally, we found that SK-RC-39 cell lines were more sensitive to sunitinib after knocking down the signature gene CDCA3, PDIA4, or SUCNR1.

Conclusions: Our comprehensive analysis of CRs gene in pRCC showed that CRs gene plays a potential role in TME, prognosis and drug resistance in pRCC. These findings may lay a foundation for further study of the regulatory role of CRs gene in pRCC, and provide a new method for evaluating prognosis and developing more effective targeted therapy.