Pan-cancer analysis of SETD2 mutation and its association with the efficacy of immunotherapy.
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ABSTRACT:
SUBMITTER: Lu M
PROVIDER: S-EPMC8203790 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: Not available
| S-EPMC7443139 | biostudies-literature
Project description:Background: The clinical implementation of immune-checkpoint inhibitors (ICIs) targeting CTLA4, PD-1, and PD-L1 has revolutionized the treatment of cancer. However, the majority of patients do not derive clinical benefit. Further development is needed to optimize the approach of ICI therapy. Immunotherapy combined with other forms of treatment is a rising strategy for boosting antitumor responses. CD93 was found to sensitize tumors to immune-checkpoint blocker therapy after the blockade of its pathway. However, its role in immune and ICB therapy across pan-cancer has remained unexplored. Methods: In this study, we provide a comprehensive investigation of CD93 expression in a pan-cancer manner involving 33 cancer types. We evaluated the association of CD93 expression with prognosis, mismatch repair, tumor mutation burden, and microsatellite instability, immune checkpoints, tumor microenvironment, and immune using multiple online datasets, including The Cancer Genome Atlas, Cancer Cell Line Encyclopedia, Genotype Tissue-Expression, cBioPortal, Tumor Immune Estimation Resource database, and Tumor Immune Single-cell Hub. Results: CD93 expression varied strongly among cancer types, and increased CD93 gene expression was associated with poor prognosis as well as higher immune factors in most cancer types. Additionally, the level of CD93 was significantly correlated with MMR, TMB, MSI, immune checkpoints, TME, and immune cell infiltration. Noticeably, our results mediated a strong positive contact between CD93 and CAFs, endothelial cells, myeloid dendritic cells, hematopoietic stem cells, mononuclear/macrophage subsets, and neutrophils while a negative correlation with Th1, MDSC, NK, and T-cell follicular helper in almost all cancers. Function analysis on CD93 revealed a link between itself and promoting cancers, inflammation, and angiogenesis. Conclusion: CD93 can function as a prognostic marker in various malignant tumors and is integral in TME and immune infiltration. Inhibition of the CD93 pathway may be a novel and promising strategy for immunotherapy in human cancer. Further explorations of the mechanisms of CD93 in the immune system may help improve cancer therapy methods.
| S-EPMC8886047 | biostudies-literature
Project description:IRAK1 is an active kinase which plays a critical role in IL-1/TLR signaling pathway involved in inflammation and innate immune response. Recently, increasing evidence supports a potential role of IRAK1 in cancer progression. However, no immunological pan-cancer analysis of IRAK1 is available. We aimed to explore the prognostic value and the immunological functions of IRAK1. A series of datasets including The Cancer Genome Atlas, GEPIA2, cBioPortal, HPA, TIMER2.0 were performed to explore the oncogenic and immunological roles of IRAK1, including the relationship between IRAK1 and prognosis, genetic mutation, GO and KEGG enrichment pathway analysis, immune state of different tumors, The results showed that IRAK1 levels were upregulated in more than 20 types of cancers compared to the normal tissues. IRAK1 expression was associated with poorer prognosis in different cancer types. For the most frequent DNA alteration of IRAK1 is amplification. And the result of the enrichment analysis suggested that IRAK1 related to immune checkpoint pathway in cancer. IRAK1 inhibitor pacritinib inhibit proliferation and upregulate PD-L1 expression in different cancer cell lines. Moreover, the patients who receiving anti-PD-L1 therapy with low IRAK1 expression had a better prognosis, and the objective response rate to anti-PD-L1 therapy was higher in the low IRAK1 group than in the high IRAK1 group in IMvigor210 cohort. Our study reveals that IRAK1 can function as a prognostic marker in various malignant tumors. And pacritinib upregulated PD-L1 expression in several cancer cell lines, which indicating that IRAK1 can be used as a reliable marker to predict the efficacy of immunotherapy.
| S-EPMC9163706 | biostudies-literature
Project description:There is conflicting data regarding the role of PBAF complex mutations and response to immune checkpoint blockade (ICB) therapy in clear cell renal cell carcinoma (ccRCC) and other solid tumors. We assess the prevalence of PBAF complex mutations from two large cohorts including the pan-cancer TCGA project (n?=?10,359) and the MSK-IMPACT pan-cancer immunotherapy cohort (n?=?3700). Across both cohorts, PBAF complex mutations, predominantly PBRM1 mutations, are most common in ccRCC. In multivariate models of ccRCC patients treated with ICB (n?=?189), loss-of-function (LOF) mutations in PBRM1 are not associated with overall survival (OS) (HR?=?1.24, p?=?0.47) or time to treatment failure (HR?=?0.85, p?=?0.44). In a series of 11 solid tumors (n?=?2936), LOF mutations are not associated with improved OS in a stratified multivariate model (HR?=?0.9, p?=?0.7). In a current series of solid tumors treated with ICB, we are unable to demonstrate favorable response to ICB in patients with PBAF complex mutations.
| S-EPMC7441387 | biostudies-literature
Project description:Paired immunoglobulin-like type 2 receptor alpha (PILRA) plays a vital role in regulating broad immune responses. However, the roles of PILRA in cancer immunity remain unexplored yet. In the current study, we comprehensively analyzed the oncogenic and immunologic roles of PILRA at a pan-cancer level based on the Cancer Genome Atlas and Gene Expression Omnibus datasets. PILRA was significantly dysregulated and frequently mutated in pan-cancer. Its expression and mutation status significantly impacted patient prognosis in several cancers. Besides, PILRA expression was positively correlated with ESTIMATE scores and the abundances of tumor-infiltrating immune cells. Concurrently, PILRA expression was significantly associated with predictive biomarkers of cancer immunotherapy, and positively correlated with the prognostic outcomes of cancer patients receiving immunotherapy. Mechanistically, enrichment analysis implied that PILRA might be involved in the regulation of immune response and metabolic process. This study uncovered the immunological roles of PILRA in cancers and its potential as a novel biomarker and therapeutic target for cancer immunotherapy.
| S-EPMC10471747 | biostudies-literature
Project description:Senescence is a double-edged sword in tumorigenesis and affects the immunotherapy response through the modulation of the host's immune system. However, there is currently a lack of comprehensive analysis of the senescence-related genes (SRGs) in human cancers, and the predictive role of senescence in cancer immunotherapy response has not been explored. The multi-omics approaches were performed in this article to conduct a systematic pan-cancer genomic analysis of SRGs in cancer. In addition, we calculated the generic senescence score (SS) to quantify the senescence levels in cancers and explored the correlations of SS with cancer prognosis, biological processes, and tumor microenvironment (TME). The gene signatures were deregulated in multiple cancers and indicated a context-dependent correlation with prognosis, tumor-immune evasion, and response to therapy across various tumor types. Further analysis disclosed that SS was positively associated with the infiltration levels of immune suppressive cells, including induced Tregs (iTregs), central memory Ts (Tcms), and natural Tregs (nTregs), and negatively associated with immune killer cells, including natural killers (NKs) and mucosal-associated invariant Ts (MAITs). Moreover, the SS was significantly correlated with tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), immune-related genes, and immune checkpoints and had a predictive value of immunotherapy response. Thus, the expression of SRGs was involved in resistance to several anticancer drugs. Our work illustrates the characterization of senescence across various malignancies and highlights the potential of senescence as a biomarker of the response to immunotherapy.
| S-EPMC9334796 | biostudies-literature
Project description:In cancer genomics, recurrence of mutations in independent tumor samples is a strong indicator of functional impact. However, rare functional mutations can escape detection by recurrence analysis owing to lack of statistical power. We enhance statistical power by extending the notion of recurrence of mutations from single genes to gene families that share homologous protein domains. Domain mutation analysis also sharpens the functional interpretation of the impact of mutations, as domains more succinctly embody function than entire genes. By mapping mutations in 22 different tumor types to equivalent positions in multiple sequence alignments of domains, we confirm well-known functional mutation hotspots, identify uncharacterized rare variants in one gene that are equivalent to well-characterized mutations in another gene, detect previously unknown mutation hotspots, and provide hypotheses about molecular mechanisms and downstream effects of domain mutations. With the rapid expansion of cancer genomics projects, protein domain hotspot analysis will likely provide many more leads linking mutations in proteins to the cancer phenotype.
| S-EPMC4982675 | biostudies-literature
Project description: Not available
| S-EPMC10884410 | biostudies-literature
Project description:BackgroundATP7B is a copper-transporting protein that contributes to the chemo-resistance of human cancer cells. It remains unclear what the molecular mechanisms behind ATP7B are in cancer, as well as its role in human pan-cancer studies.MethodsOur study evaluated the differential expression of ATP7B in cancer and paracancerous tissues based on RNA sequencing data from the GTEx and TCGA. Kaplan-Meier and Cox proportional hazards regressions were used to estimate prognostic factors associated with ATP7B.The correlations between the expression of ATP7B and immune cell infiltration, tumor mutation burden, microsatellite instability and immune checkpoint molecules were analyzed. Co-expression networks and mutations in ATP7B were analyzed using the web tools. An analysis of ATP7B expression difference on drug sensitivity on tumor cells was performed using the CTRP, GDSC and CMap database.ResultsATP7B expression differed significantly between cancerous and paracancerous tissues. The abnormal expression of ATP7B was linked to prognosis in LGG and KIRC. Infiltration of immune cells, tumor mutation burden, microsatellite instability and immunomodulators had all been linked to certain types of cancer. Cancer cells exhibited a correlation between ATP7B expression and drug sensitivity.ConclusionATP7B might be an immunotherapeutic and prognostic biomarker based on its involvement in cancer occurrence and development.
| S-EPMC10687837 | biostudies-literature
Project description:The relation between tumor mutation burden (TMB) and outcome of cancer patients receiving immunotherapy has been reported. This study aimed to evaluate the prognostic role of TMB in cancer patients receiving immunotherapy. Databases including Embase, PubMed, and the Cochrane library were systematically searched to identify potentially eligible studies until Sep 2018 without language limitation. Studies assessing high versus low TMB in predicting survival of various cancer patients were selected. The pooled analyses were conducted using hazard ratio (HR) of high versus low TMB for overall survival (OS) and progression-free survival (PFS), and the odds ratio (OR) for overall response rate (ORR). The primary endpoint was OS. Secondary outcomes were PFS and ORR. A total of 45 studies consisting of 103078 cancer patients were included. The combined results showed that high TMB was associated with better OS (HR = 0.40; 95% confidence interval (CI):0.30-0.53; p< .00001), PFS (HR = 0.37; 95% CI: 0.26-0.53; p< .00001) and ORR (OR = 4.62; 95%CI: 2.90-7.34; p< .0001) when treated with immunotherapy. In studying patients with high TMB, these patients had improved OS (HR = 0.69; 95%CI: 0.47-1.03; p= .07) when comparing immunotherapy to chemotherapy. Subgroup analyses suggested that the prognostic role of TMB was independent of cancer types and TMB detection methods (all p< .05). Our findings suggest that high TMB is associated with better survival in cancer patients receiving immunotherapy. For cancer patients with high TMB, immunotherapy could be considered.
| S-EPMC6685508 | biostudies-literature