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ORIGINAL RESEARCH article
Front. Genet.
Sec. Cancer Genetics and Oncogenomics
Volume 15 - 2024 |
doi: 10.3389/fgene.2024.1447139
Revealing the Characteristics of SETD2-Mutated Clear Cell Renal Cell Carcinoma through Tumor Heterogeneity Analysis
Provisionally accepted- 1 Meizhou Clinical Institute of Shantou University Medical College, Meizhou, China
- 2 Department of Urology, Meizhou People's Hospital, Meizhou, Guangdong Province, China
Renal cell carcinoma (RCC) is the most prevalent type of malignant kidney tumor in adults, with clear cell renal cell carcinoma (ccRCC) comprising about 75% of all cases. The SETD2 gene, which is involved in the modification of histone proteins, is often found to have alterations in ccRCC. Yet, our understanding of how these SETD2 mutations affect ccRCC characteristics and behavior within the tumor microenvironment is still not fully understood.We conducted a detailed analysis of single-cell RNA sequencing (scRNA-seq) data from ccRCC. First, the data was preprocessed using the Python package, 'scanpy'. High variability genes were pinpointed through Pearson's correlation coefficient. Dimensionality reduction and clustering identification were performed using Principal Component Analysis (PCA) and the Leiden algorithm. Malignant cell identification was conducted with the 'InferCNV' R package, while cell trajectories and intercellular communication were depicted using the Python packages 'VIA' and 'cellphoneDB'. We then employed the R package 'Deseq2' to determine differentially expressed genes (DEGs) between groups. Using high-dimensional weighted gene correlation network analysis (hdWGCNA), co-expression modules were identified. We intersected these modules with DEGs to establish prognostic models through univariate Cox and the least absolute shrinkage and selection operator (LASSO) method.We identified 69 and 53 distinctive cell clusters, respectively. These were classified further into 12 unique cell types. This analysis highlighted the presence of an abnormal tumor sub-cluster (MT+ group), identified by high mitochondrial-encoded protein gene expression and an indication of unfavorable prognosis. Investigation of cellular interactions spotlighted significant interactions between the MT+ group and endothelial cells, macrophaes. In addition, we developed a prognostic model based on 6 characteristic genes. Notably, risk scores derived from these genes correlated significantly with various clinical features. Finally, a nomogram model was established to facilitate more accurate outcome prediction, incorporating four independent risk factors.Our findings provide insight into the crucial transcriptomic characteristics of ccRCC associated with SETD2 mutation. We discovered that this mutation-induced subcluster could stimulate M2 polarization in macrophages, suggesting a heightened propensity for metastasis. Moreover, our prognostic model demonstrated effectiveness in forecasting overall survival for ccRCC patients, thus presenting a valuable clinical tool.
Keywords: Clear cell renal cell carcinoma, ScRNA-seq, SETD2, macrophage, prognosis
Received: 11 Jun 2024; Accepted: 08 Jul 2024.
Copyright: © 2024 Peng, Xie, Jiang, Zhang and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Nanhui Chen, Meizhou Clinical Institute of Shantou University Medical College, Meizhou, China
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