J Cancer 2021; 12(11):3265-3276. doi:10.7150/jca.51812

Research Paper

Identification of an apoptosis-related prognostic gene signature and molecular subtypes of clear cell renal cell carcinoma (ccRCC)

Weimin Zhong1, Fengling Zhang1, Chaoqun Huang1, Yao Lin2✉, Jiyi Huang1✉

1. The Fifth Hospital of Xiamen, Xiamen 361101, Fujian Province, China.
2. Key Laboratory of Optoelectronic Science and Technology for Medicine of Ministry of Education, College of Life Sciences, Fujian Normal University, Fuzhou 350117, Fujian Province, China.

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Zhong W, Zhang F, Huang C, Lin Y, Huang J. Identification of an apoptosis-related prognostic gene signature and molecular subtypes of clear cell renal cell carcinoma (ccRCC). J Cancer 2021; 12(11):3265-3276. doi:10.7150/jca.51812. Available from https://www.jcancer.org/v12p3265.htm

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Previously studies have shown that apoptosis-related genes play an essential role in normal cell turnover, maintaining the immune system function, and inducing cell death. However, their prognostic roles in clear cell renal cell carcinoma (ccRCC) have not been thoroughly investigated. In the present study, apoptosis-related genes expression profiles from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) database were used as training dataset and external validation dataset, respectively. According to the systematical analysis of the apoptosis-related gene expression profile, we constructed a gene signature to determine the role of apoptosis-related genes in the survival of ccRCC. We discovered that patients in the low-risk group have a better survival than high-risk group and the signature could serve as an independent prognostic factor. A nomogram, including a signature and clinical factors, were constructed to estimate the individual survival probability. The Gene set enrichment analysis (GSEA) identified some significant pathways which may contribute to understanding the underlying mechanism of ccRCC. In addition, the prognostic efficiency of the risk model was further validated in the disease free survival (DFS) and the ICGC dataset, respectively. We also identified three molecular subtypes (named C1, C2, and C3) based on apoptosis-related gene expression. We found that C1 was corresponding to a worse survival outcome and showed a high drug sensitivity of sorafenib and sunitinib. C2 and C3 were corresponding to a better survival outcome and presented a low drug sensitivity to sorafenib and sunitinib. Moreover, we found that C2 and C3 have more likelihood to be respond to immunotherapy. Together, the apoptosis-related gene signature and three molecular subtypes may promote the understanding of the underlying molecular mechanism of ccRCC, and provided reference for developing individualized treatment of the ccRCC patients.

Keywords: clear cell renal cell carcinoma, apoptosis, gene signature, nomogram, molecular subtypes, drug sensitivity, immunotherapy.