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. 2022 Mar 17:12:840410.
doi: 10.3389/fonc.2022.840410. eCollection 2022.

A Novel Gene Signature of Tripartite Motif Family for Predicting the Prognosis in Kidney Renal Clear Cell Carcinoma and Its Association With Immune Cell Infiltration

Di Zheng  1 , Yunlong Zhang  1 , Yuqi Xia  1 , Fan Cheng  1
Affiliations

A Novel Gene Signature of Tripartite Motif Family for Predicting the Prognosis in Kidney Renal Clear Cell Carcinoma and Its Association With Immune Cell Infiltration

Di Zheng et al. Front Oncol. .

Abstract

Given the importance of tripartite motif (TRIM) proteins in diverse cellular biological processes and that their dysregulation contributes to cancer progression, we constructed a robust TRIM family signature to stratify patients with kidney renal clear cell carcinoma (KIRC). Transcriptomic profiles and corresponding clinical information of KIRC patients were obtained from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) databases. Prognosis-related TRIM family genes were screened and used to construct a novel TRIM family-based signature for the training cohort. The accuracy and generalizability of the prognostic signature were assessed in testing, entire, and external ICGC cohorts. We analyzed correlations among prognostic signatures, tumor immune microenvironment, and immune cell infiltration. The results of univariate Cox regression and Kaplan-Meier survival analyses revealed 27 TRIMs that were robustly associated with the prognosis of patients with KIRC. We applied Lasso regression and multivariate Cox regression analyses to develop a prognostic signature containing the TRIM1, 13, 35, 26, 55, 2, 47, and 27 genes to predict the survival of patients with KIRC. The accuracy and generalizability of this signature were confirmed in internal and external validation cohorts. We also constructed a predictive nomogram based on the signature and the clinicopathological characteristics of sex, age, and T and M status to aid clinical decision-making. We analyzed immune cell infiltration analysis and found that CD8 T cells, memory resting CD4 T cells, and M2 macrophages were the most enriched components in the KIRC tumor immune microenvironment. A higher level of immune infiltration by plasma cells, follicular helper T cells, and activated NK cells, and a lower level of immune infiltration by memory resting CD4 T cells, M1 and M2 macrophages, and resting dendritic cells were associated with higher risk scores. Overall, our eight-gene TRIM family signature has sufficient accuracy and generalizability for predicting the overall survival of patients with KIRC. Furthermore, this prognostic signature is associated with tumor immune status and distinct immune cell infiltrates in the tumor microenvironment.

Keywords: KIRC; immune cell infiltration; prognosis; signature; tripartite motif family.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Identification of prognosis-related TRIMs in KIRC and construction of a protein-protein interaction network. (A) The expression profile of TRIMs in tumor tissues and adjacent normal tissues. (B) Venn plot showing the differentially expressed TRIMs between KIRC tissues and adjacent non-tumor tissues, and prognosis-related TRIMs. (C) Volcano plot showing the prognosis-related TRIMs. (D) Correlation heatmap of the 27 prognosis-related TRIMs. (E) Protein-protein interaction network of the 27 prognosis-related TRIMs. (F) Hub genes in the PPI network.
Figure 2
Figure 2
Construction of a novel eight-gene signature of TRIM family in the training cohort. (A) Lasso coefficients profiles of the prognosis-related TRIMs. (B) The association between deviance and log (lambda). (C) The coefficients of the eight TRIM genes. (D) Risk score distribution of KIRC patients in training cohort. (E) The distribution of survival time and survival status of KIRC patients in training cohort. (F) The expression profile of the eight TRIM genes. (G) Kaplan-Meier survival analysis in the training cohort. (H) Time-dependent ROC curve for 1-, 2-, and 3-year predictions in training cohort.
Figure 3
Figure 3
Validation of the eight-gene signature of TRIM family in the internal validation cohorts. (A, B) Risk score distribution of KIRC patients in testing and entire cohorts. (C, D) The distribution of survival time and survival status of KIRC patients in testing and entire cohorts. (E, F) The expression profile of the eight TRIM genes in testing and entire cohorts. (G, H) Kaplan-Meier survival analysis in testing and entire cohorts. (I, J) Time-dependent ROC curve for 1-, 2-, and 3-year predictions in testing and entire cohorts.
Figure 4
Figure 4
Validation of the eight-gene signature of TRIM family in external ICGC cohort. (A) Risk score distribution of KIRC patients in ICGC cohort. (B) The distribution of survival time and survival status of KIRC patients in ICGC cohort. (C) The expression profile of the eight TRIM genes in ICGC cohort. (D) Kaplan-Meier survival analysis in ICGC cohort. (E) Time-dependent ROC curve for 1-, 2-, and 3-year predictions in ICGC cohort.
Figure 5
Figure 5
KM survival analysis of subgroups stratified by gender (A), age (B), grade (C), stage (D), and T and M status (E, F).
Figure 6
Figure 6
Construction and validation of a nomogram in TCGA and ICGC KIRC cohorts. (A) The nomogram comprising clinicopathological factors including gender, age, T and M status, and risk score based on the eight-TRIM gene signature. (B, C) The calibration curves displayed the concordance between predicted and observed 1-, 3-, and 5-year overall survival in TCGA (B) and ICGC (C) KIRC cohorts.
Figure 7
Figure 7
Identification of risk-related differential expressed genes and functional enrichment analysis. (A) Venn plot exhibiting differentially expressed genes between high- and low-risk groups in TCGA and ICGC cohorts. (B–C) The expression profiles of the differentially expressed genes in TCGA and ICGC cohorts. (D) GO enrichment analysis of the differentially expressed genes. (E) KEGG enrichment analysis of the differentially expressed genes. (F, G) Gene set enrichment analysis in TCGA and ICGC cohorts.
Figure 8
Figure 8
The signature was correlated with tumor immune cell infiltration in TCGA KIRC cohort. (A) Stacked bar chart showing the abundance of 22 immune cell types in each KIRC sample of the TCGA cohort. (B) The correlation heatmap of the infiltrating immune cells in the TCGA cohort. (C, D) Heatmap and violin plot exhibiting immune cell infiltrates in KIRC patients at high- and low-risk groups.
Figure 9
Figure 9
Expression and survival analysis of the eight genes of TRIM family. (A–H) The expression levels of TRIM1, TRIM2, TRIM26, TRIM13, TRIM27, TRIM55, TRIM47, and TRIM35 in KIRC tumor tissues and adjacent normal tissues. (I–P) Kaplan-Meier curve analyses of the eight genes in TCGA KIRC cohort.
Figure 10
Figure 10
qRT-PCR was employed to detect the expression levels of TRIM1 (A), TRIM2 (B), TRIM26 (C), TRIM13 (D), TRIM27 (E), TRIM55 (F), TRIM47 (G), and TRIM35 (H) in clinical KIRC samples. *P < 0.05, **P < 0.01, ***P < 0.001.
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