Chuanjie Zhang1, Zongtai Li2, Feng Qi3, Xin Hu4, Jun Luo5. 1. Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. 2. Department of Medical Oncology, Gaozhou People's Hospital, Gaozhou 525200, China. 3. Department of Urology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China. 4. First Clinical Medical College of Nanjing Medical University, Nanjing 210029, China. 5. Department of Urology, Shanghai Fourth People's Hospital affiliated to Tongji University School of Medicine, Shanghai 200081, China.
Abstract
BACKGROUND: Whether tumor mutation burden (TMB) correlated with improved survival outcomes or promotion of immunotherapies remained controversy in various malignancies. We aimed to investigate the prognosis of TMB and the potential association with immune infiltrates in clear cell renal cell carcinoma (ccRCC). METHODS: We downloaded the somatic mutation data of 336 ccRCC patients from the Cancer Genome Atlas (TCGA) database, and analyzed the mutation profiles with "maftools" package. TMB was calculated and we classified the samples into high-TMB and low-TMB group. Differential analysis was conducted to compare the expression profiles between two groups using "limma" package, and we identified the 9 hub TMB-related signature from batch survival analysis. Gene ontology (GO) analysis and Gene Set Enrichment Analysis (GSEA) were performed to screen significantly enriched pathways between two groups. Based on the TIMER database, we further assessed the relationships of the mutants of 9 TMB-related signature with immune infiltration levels in ccRCC. Besides, we utilized the "CIBERSORT" package to estimate the abundance of 22 immune fractions between low- and high-TMB groups, and the significant difference were determined by Wilcoxon rank-sum test. Furthermore, Cox regression model combined with survival analysis were used to evaluate the prognostic value of immune cells. Last, we constructed a Tumor Mutation Burden Prognostic Index (TMBPI) from multivariate Cox results and Receiver Operating Characteristic (ROC) curve was drawn to assess the predictive accuracy. RESULTS: Single nucleotide polymorphism (SNP) occurred more frequently than insertion or deletion, and C>T was the most common of SNV in ccRCC. Higher TMB levels conferred poor survival outcomes, associated with higher tumor grades and advanced pathological stages. A total of 1,265 differentially expressed genes were obtained and top 19 immune-related genes were identified in Venn diagram. GSEA revealed that patients in higher TMB groups correlated with MAPK signaling pathway, Wnt signaling pathway and pathway in cancers. Moreover, we identified 9 hub TMB-related immune genes related with survival and mutants of 9 signature were associated with lower immune infiltrates. In addition, infiltration levels of CD8+ T cell, CD4+ memory resting T cell, M1 and M2 macrophages, as well as dendritic resting cells in high-TMB group were lower than that in low-TMB group, especially the level of CD8+ T cell and macrophage correlated negatively with prognosis of ccRCC. Last, the TMBPI was constructed and the AUC of ROC curve was 0.666. CONCLUSIONS: Higher TMB correlated with poor survival outcomes and might inhibit the immune infiltrates in ccRCC. The mutants of 9 hub TMB-related immune signature conferred lower immune cells infiltration which deserved further validation. 2019 Annals of Translational Medicine. All rights reserved.
BACKGROUND: Whether tumor mutation burden (TMB) correlated with improved survival outcomes or promotion of immunotherapies remained controversy in various malignancies. We aimed to investigate the prognosis of TMB and the potential association with immune infiltrates in clear cell renal cell carcinoma (ccRCC). METHODS: We downloaded the somatic mutation data of 336 ccRCC patients from the Cancer Genome Atlas (TCGA) database, and analyzed the mutation profiles with "maftools" package. TMB was calculated and we classified the samples into high-TMB and low-TMB group. Differential analysis was conducted to compare the expression profiles between two groups using "limma" package, and we identified the 9 hub TMB-related signature from batch survival analysis. Gene ontology (GO) analysis and Gene Set Enrichment Analysis (GSEA) were performed to screen significantly enriched pathways between two groups. Based on the TIMER database, we further assessed the relationships of the mutants of 9 TMB-related signature with immune infiltration levels in ccRCC. Besides, we utilized the "CIBERSORT" package to estimate the abundance of 22 immune fractions between low- and high-TMB groups, and the significant difference were determined by Wilcoxon rank-sum test. Furthermore, Cox regression model combined with survival analysis were used to evaluate the prognostic value of immune cells. Last, we constructed a Tumor Mutation Burden Prognostic Index (TMBPI) from multivariate Cox results and Receiver Operating Characteristic (ROC) curve was drawn to assess the predictive accuracy. RESULTS: Single nucleotide polymorphism (SNP) occurred more frequently than insertion or deletion, and C>T was the most common of SNV in ccRCC. Higher TMB levels conferred poor survival outcomes, associated with higher tumor grades and advanced pathological stages. A total of 1,265 differentially expressed genes were obtained and top 19 immune-related genes were identified in Venn diagram. GSEA revealed that patients in higher TMB groups correlated with MAPK signaling pathway, Wnt signaling pathway and pathway in cancers. Moreover, we identified 9 hub TMB-related immune genes related with survival and mutants of 9 signature were associated with lower immune infiltrates. In addition, infiltration levels of CD8+ T cell, CD4+ memory resting T cell, M1 and M2 macrophages, as well as dendritic resting cells in high-TMB group were lower than that in low-TMB group, especially the level of CD8+ T cell and macrophage correlated negatively with prognosis of ccRCC. Last, the TMBPI was constructed and the AUC of ROC curve was 0.666. CONCLUSIONS: Higher TMB correlated with poor survival outcomes and might inhibit the immune infiltrates in ccRCC. The mutants of 9 hub TMB-related immune signature conferred lower immune cells infiltration which deserved further validation. 2019 Annals of Translational Medicine. All rights reserved.
Authors: Freddie Bray; Jacques Ferlay; Isabelle Soerjomataram; Rebecca L Siegel; Lindsey A Torre; Ahmedin Jemal Journal: CA Cancer J Clin Date: 2018-09-12 Impact factor: 508.702
Authors: Cyriac Kandoth; Michael D McLellan; Fabio Vandin; Kai Ye; Beifang Niu; Charles Lu; Mingchao Xie; Qunyuan Zhang; Joshua F McMichael; Matthew A Wyczalkowski; Mark D M Leiserson; Christopher A Miller; John S Welch; Matthew J Walter; Michael C Wendl; Timothy J Ley; Richard K Wilson; Benjamin J Raphael; Li Ding Journal: Nature Date: 2013-10-17 Impact factor: 49.962
Authors: Ivan de Kouchkovsky; Li Zhang; Errol J Philip; Francis Wright; Daniel M Kim; Divya Natesan; Daniel Kwon; Hansen Ho; Son Ho; Emily Chan; Sima P Porten; Anthony C Wong; Arpita Desai; Franklin W Huang; Jonathan Chou; David Y Oh; Raj S Pruthi; Lawrence Fong; Eric J Small; Terence W Friedlander; Vadim S Koshkin Journal: J Immunother Cancer Date: 2021-05 Impact factor: 13.751
Authors: Michela Roberto; Andrea Botticelli; Martina Panebianco; Anna Maria Aschelter; Alain Gelibter; Chiara Ciccarese; Mauro Minelli; Marianna Nuti; Daniele Santini; Andrea Laghi; Silverio Tomao; Paolo Marchetti Journal: Front Oncol Date: 2021-04-22 Impact factor: 6.244