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Characterization of Hypoxia-Related Molecular Subtypes in Clear Cell Renal Cell Carcinoma to Aid Immunotherapy and Targeted Therapy via Multi-Omics Analysis.

ABSTRACT: Objective: Tumor hypoxia is a key factor in resistance to anti-cancer treatment. Herein, this study aimed to characterize hypoxia-related molecular subtypes and assess their correlations with immunotherapy and targeted therapy in clear cell renal cell carcinoma (ccRCC). Materials: We comprehensively analyzed copy number variation (CNV), somatic mutation, transcriptome expression profile and clinical information for ccRCC from TCGA and ICGC databases. Based on 98 prognosis-related hypoxia genes, samples were clustered using unsupervized non-negative matrix factorization (NMF) analysis. We characterized the differences between subtypes concerning prognosis, CNV, somatic mutations, pathways, immune cell infiltrations, stromal/immune scores, tumor purity, immune checkpoint inhibitors (ICI), response to immunotherapy and targeted therapy and CXC chemokines. Based on differentially expressed genes (DEGs) between subtypes, a prognostic signature was built by LASSO Cox regression analysis, followed by construction of a nomogram incorporating the signature and clinical features. Results: Two hypoxia-related molecular subtypes (C1 and C2) were constructed for ccRCC. Differential CNV, somatic mutations and pathways were found between subtypes. C2 exhibited poorer prognosis, higher immune/stromal scores, and lower tumor purity than C1. Furthermore, C2 had more sensitivity to immunotherapy and targeted therapy than C1. The levels of CXCL1/2/3/5/6/8 chemokines in C2 were distinctly higher than in C1. Consistently, DEGs between subtypes were significantly enriched in cytokine-cytokine receptor interaction and immune responses. This subtype-specific signature can independently predict patients' prognosis. Following verification, the nomogram could be utilized for personalized prediction of the survival probability. Conclusion: Our findings characterized two hypoxia-related molecular subtypes for ccRCC, which can assist in identifying high-risk patients with poor clinical outcomes and patients who can benefit from immunotherapy or targeted therapy.

SUBMITTER: Zhong W

PROVIDER: S-EPMC8267011 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Characterization of Hypoxia-Related Molecular Subtypes in Clear Cell Renal Cell Carcinoma to Aid Immunotherapy and Targeted Therapy via Multi-Omics Analysis.

Zhong Weimin W Zhong Hongbin H Zhang Fengling F Huang Chaoqun C Lin Yao Y Huang Jiyi J

Frontiers in molecular biosciences 20210625

Objective: Tumor hypoxia is a key factor in resistance to anti-cancer treatment. Herein, this study aimed to characterize hypoxia-related molecular subtypes and assess their correlations with immunotherapy and targeted therapy in clear cell renal cell carcinoma (ccRCC). Materials: We comprehensively analyzed copy number variation (CNV), somatic mutation, transcriptome expression profile and clinical information for ccRCC from TCGA and ICGC databases. Based on 98 prognosis-related h ...[more]

PMID: 34250018

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Project description:Ubiquitin modification is the most common protein post-translational modification (PTM) process in organisms, and 1332 ubiquitin regulators have been identified in humans. Ubiquitin regulators, especially E3 ligases and deubiquitinases, are widely involved in immune processes. This study aims to explore the ubiquitin modification features of clear cell renal cell carcinoma (ccRCC) and to elucidate the role of such ubiquitin modifications in shaping anti-tumor immunity and individual benefits from immune checkpoint blockade (ICB). A comprehensive analysis was performed in the TCGA cohort (n = 530) and GEO cohort (n = 682). RNA sequencing data of 758 differentially expressed regulators, which was validated by the proteomics data, was used for k-means unsupervised consensus clustering and three ubiquitin patterns of ccRCC were identified. Then, we focused on the ubiquitin modification and tumor progression signatures, immune infiltration characteristics, and prognostic value. The three patterns with different ubiquitin modification signatures correspond to "immune desert phenotype," "immune resistance phenotype," and "immune-inflammatory phenotype," respectively. To facilitate clinical application, we constructed a ubiquitin score to evaluate individual patients' ubiquitination outcome, and it was demonstrated to be an independent risk factor for overall survival (OS) in multivariate Cox analysis. It was found that the high score group was correlated to higher immune cells infiltrating level and PD-1/PD-L1/CTLA-4 expression. More importantly, we found that the high score group was predicted to be sensitive to anti-PD-1 treatment, while the low-score group showed lower predicted IC50 values in treatment with Pazopanib and Axitinib. In summary, this study elucidated the potential link between ubiquitin modification and immune infiltration landscape of ccRCC for the first time and provided a new assessment protocol for the precise selection of treatment strategies for patients with advanced ccRCC.

Project description:Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer and has strong immunogenicity. A systematically investigation of the tumor microenvironment (TME) in ccRCC could contribute to help clinicians develop personalized treatment and facilitate clinical decision-making. In this study, we analyzed the immune-related subtype of ccRCC on the basis of immune-related gene expression data in The Cancer Genome Atlas (TCGA, N = 512) and E-MTAB-1980 (N = 101) dataset, respectively. As a result, two subtypes (C1 and C2) were identified by performing non-negative matrix factorization clustering. Subtype C1 was characterized by increased advance ccRCC cases and immune-related pathways. A higher immune score, stromal score, TMB value, Tumor Immune Dysfunction and Exclusion (TIDE) prediction score, and immune checkpoint genes expression level were also observed in C1. In addition, the C1 subtype might benefit from chemotherapy and immunotherapy. The patients in subtype C2 had more metabolism-related pathways, higher tumor purity, and a better prognosis. Moreover, some small molecular compounds for the treatment of ccRCC were identified between the two subtypes by using the Connectivity Map (CMap) database. Finally, we constructed and validated an immune-related (IR) score to evaluate immune modification individually. A high IR score corresponded to a favorable prognosis compared to a low IR score, while more advanced tumor stage and grade cases were enriched in the low IR score group. The two IR score groups also showed a distinct divergence among immune status, TME, and chemotherapy. The external validation dataset (E-MTAB-1980) and another immunotherapy cohort (IMvigor 210) demonstrated that patients in the high IR score group had a significantly prolonged survival time and clinical benefits compared to the low IR score group. Together, characterization of molecular heterogeneity and IR signature may help develop new insights into the TME of ccRCC and provide new strategies for personalized treatment.

Project description:BackgroundClear cell renal cell carcinoma (ccRCC) is a malignant disease containing tumor-infiltrating lymphocytes. Reactive oxygen species (ROS) are present in the tumor microenvironment and are strongly associated with cancer development. Nevertheless, the role of ROS-related genes in ccRCC remains unclear.MethodsWe describe the expression patterns of ROS-related genes in ccRCC from The Cancer Genome Atlas and their alterations in genetics and transcription. An ROS-related gene signature was constructed and verified in three datasets and immunohistochemical staining (IHC) analysis. The immune characteristics of the two risk groups divided by the signature were clarified. The sensitivity to immunotherapy and targeted therapy was investigated.ResultsOur signature was constructed on the basis of glutamate-cysteine ligase modifier subunit (GCLM), interaction protein for cytohesin exchange factors 1 (ICEF1), methionine sulfoxide reductase A (MsrA), and strawberry notch homolog 2 (SBNO2) genes. More importantly, protein expression levels of GCLM, MsrA, and SBNO2 were detected by IHC in our own ccRCC samples. The high-risk group of patients with ccRCC suffered lower overall survival rates. As an independent predictor of prognosis, our signature exhibited a strong association with clinicopathological features. An accurate nomogram for improving the clinical applicability of our signature was constructed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that the signature was closely related to immune response, immune activation, and immune pathways. The comprehensive results revealed that the high-risk group was associated with high infiltration of regulatory T cells and CD8+ T cells and more benefited from targeted therapy. In addition, immunotherapy had better therapeutic effects in the high-risk group.ConclusionOur signature paved the way for assessing prognosis and developing more effective strategies of immunotherapy and targeted therapy in ccRCC.

Dataset Information

Characterization of Hypoxia-Related Molecular Subtypes in Clear Cell Renal Cell Carcinoma to Aid Immunotherapy and Targeted Therapy via Multi-Omics Analysis.

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Characterization of Hypoxia-Related Molecular Subtypes in Clear Cell Renal Cell Carcinoma to Aid Immunotherapy and Targeted Therapy <i>via</i> Multi-Omics Analysis.

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