Identification of a Methylation-Regulating Genes Prognostic Signature to Predict the Prognosis and Aid Immunotherapy of Clear Cell Renal Cell Carcinoma

Abstract

Methylation is one of the most extensive modifications of biological macromolecules and affects cell-fate determination, development, aging, and cancer. Several methylation modifications, including 5-methylcytosine and N6-methyladenosine, play an essential role in many cancers. However, little is known about the relationship between methylation and the prognosis of clear cell renal cell carcinoma (ccRCC). Here, we established a methylation-regulating genes prognostic signature (MRGPS) to predict the prognoses of ccRCC patients. We obtained ccRCC samples from The Cancer Genome Atlas and identified methylation-regulatingd genes (MRGs) from the Gene Set Enrichment Analysis database. We also determined differentially expressed genes (DEGs) and performed cluster analysis to identify candidate genes. Subsequently, we established and validated an MRGPS to predict the overall survival of ccRCC patients. This was also verified in 15 ccRCC samples collected from the Fujian Provincial Hospital via quantitative real-time transcription (qRT-PCR). While 95 MRGs were differentially expressed (DEGs1) between tumor and normal tissues, 17 MRGs were differentially expressed (DEGs2) between cluster 1 and 2. Notably, 13 genes common among DEGs1 and DEGs2 were identified as hub genes. In fact, we established three genes (NOP2, NSUN6, and TET2) to be an MRGPS based on their multivariate Cox regression analysis coefficients (p < 0.05). A receiver operating characteristic curve analysis confirmed this MRGPS to have a good prognostic performance. Moreover, the MRGPS was associated with characteristics of the tumor immune microenvironment and responses to inhibitor checkpoint inhibitors. Data from “IMvigor 210” demonstrated that patients with a low MRGPS would benefit more from atelozumab (p < 0.05). Furthermore, a multivariate analysis revealed that MRGPS was an independent risk factor associated with ccRCC prognosis (p < 0.05). Notably, a nomogram constructed by combining with clinical characteristics (age, grade, stage, and MRGPS risk score) to predict the overall survival of a ccRCC patient had a favorable predictive value. Eventually, our qRT-PCR results showed that tumor tissues had higher NOP2 and NSUN6 expression levels and lower TET2 expression than normal tissues of ccRCC samples. While the proposed MRGPS comprising NOP2, NSUN6, and TET2 can be an alternative prognostic biomarker for ccRCC patients, it is a promising index for personalized ICI treatments against ccRCC.

Knocking down NSUN5 inhibits the development of clear cell renal cell carcinoma by inhibiting the p53 pathway

“…P value < 0.05 and |log2(FC)| > 1.0 indicated statistically significant results. The expression of NSUN6 and NOP2 has previously been confirmed in ccRCC [ 41 ]. Wu et al reported that both NSUN2 and NOP2 were highly expressed in ccRCC cells and tissues [ 42 ].…”

Analysis of Pyroptosis-Related Immune Signatures and Identification of Pyroptosis-Related LncRNA Prognostic Signature in Clear Cell Renal Cell Carcinoma

“…The ability of the model to correctly classify the research event was evaluated by ROC curves and concordance index (C-index). The ROC curves and C-index) were also used to compare the models we built with others ( He et al, 2021 ; Zhang F. et al, 2021 ; Chen et al, 2022 ; Sun et al, 2022 ; Zhang et al, 2022 ). The differences in the predicted survival events and the virtually observed outcomes were compared by calibration plots of the nomogram.…”

Critical roles and clinical perspectives of RNA methylation in cancer

“…Similar to m 6 A modification, m 5 C RNA methylation is also required for the regulation of the immune microenvironment in diverse cancer types. Increasing evidence has identified multiple m 5 C RNA regulators are abnormally expressed in many cancer tissues and play important roles in modulating immune functions in cancer 474–477 . In triple‐negative BC, NSUN2 has been found to be expressed in monocytes/macrophages and NSUN6, on the other hand, is expressed in Treg cells 478 .…”

“…Increasing evidence has identified multiple m 5 C RNA regulators are abnormally expressed in many cancer tissues and play important roles in modulating immune functions in cancer. 474 , 475 , 476 , 477 In triple‐negative BC, NSUN2 has been found to be expressed in monocytes/macrophages and NSUN6, on the other hand, is expressed in Treg cells. 478 Additionally, NSUN6 expression has been shown to correlate strongly with multiple immune cells, particularly CD4+ T cells, suggesting a broader role in modulating immune responses.…”