Pan-Cancer Analysis of PARP1 Alterations as Biomarkers in the Prediction of Immunotherapeutic Effects and the Association of Its Expression Levels and Immunotherapy Signatures.
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ABSTRACT:
SUBMITTER: Zhang X
PROVIDER: S-EPMC8438309 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: Piezo2 is a transmembrane-spanning ion channel protein implicated in multiple physiological processes, including cell proliferation and angiogenesis in many cell types. However, Piezo2 was recognized as representing a double-edged sword in terms of tumor growth. The prognostic and immunotherapeutic roles of Piezo2 in pan-cancer have not been reported. Methods: In this study, several databases available including the UCSC Xena database, HPA, TIDE, GSEA, and cBioportal were used to investigate the expression, alterations, associations with immune indicators, and prognostic roles of Piezo2 across pan-cancer. R software and Perl scripts were used to process the raw data acquired from the UCSC Xena database. Results: Based on processed data, our results suggested that Piezo2 expression levels were tissue-dependent in different tumor tissues. Meanwhile, the survival analysis reflected that patients suffering from KIRC, LUAD, and USC with high Piezo2 expression had good OS, while those suffering from KIRP and SARC with high Piezo2 expression had poor OS. In addition, our results showed that Piezo2 expression was associated with the infiltration of CD4+ T memory cells, mast cells, and dendritic cells. These results suggested that Piezo2 may involve tumor progression by influencing immune infiltration or regulating immune cell function. Further analysis indicated that Piezo2 could influence TME by regulating T-cell dysfunction. We also found that gene mutation was the most common genetic alteration of Piezo2. The GSEA analysis revealed that Piezo2 was associated with calcium ion transport, the activation of the immune response, antigen processing and presentation pathways. Conclusion: Our study showed the expression and prognostic features of Piezo2 and highlighted its associations with genetic alterations and immune signatures in pan-cancer. Moreover, we provided several novel insights for further research on the therapeutic potential of Piezo2.
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Project description:Molecular subtyping is expected to enable bladder cancer (BC) precise treatment. However, reliable subtyping strategies for clinical application remains defective and controversial. Given the significance of tumor immune dysfunction and exclusion (TIDE) in tumor immune escape and immunotherapy, we aimed to develop a novel TIDE-based subtyping method to facilitate personalized management. Transcriptome data of BC was used to evaluate the heterogeneity and the status of TIDE patterns. We identified 69 TIDE biomarker genes and classified BC samples into three subtypes using consensus clustering. Subtype I showed the lowest TIDE status and malignancy with the best prognosis and highest sensitivity to immune checkpoint blockade (ICB) treatment, which was enriched of metabolic related signaling pathways. Subtype III represented the highest TIDE status and malignancy with the poorest prognosis and resistance to ICB treatment, resulting from its inhibitory immune microenvironment and T cell terminal exhaustion. Subtype II was in a transitional state with intermediate TIDE level, malignancy, and prognosis. We further confirmed the existence and characteristics of our novel TIDE subtypes using real-world BC samples. This subtyping method was proved to be more efficient than previous known methods in identifying non-responders to immunotherapy. We also propose that combining our TIDE subtypes with known biomarkers can potentially improve the sensitivity and specificity of these biomarkers. Moreover, besides guiding ICB treatment, this classification approach can assist in selecting the frontline or recommended drugs. Finally, we confirmed that the TIDE subtypes are conserved across the pan-tumors. In conclusion, our novel TIDE-based subtyping method can serve as a powerful clinical tool for BC and pan-cancer patients, and potentially guiding personalized therapy decisions for selecting potential beneficiaries and excluding resistant patients of ICB therapy.
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Project description:Importance:Long noncoding RNAs (lncRNAs) are involved in innate and adaptive immunity in cancer by mediating the functional state of immunologic cells, pathways, and genes. However, whether lncRNAs are associated with immune molecular classification and clinical outcomes of cancer immunotherapy is largely unknown. Objectives:To explore lncRNA-based immune subtypes associated with survival and response to cancer immunotherapy and to present a novel lncRNA score for immunotherapy prediction using computational algorithms. Design, Setting, and Participants:In this cohort study, an individual patient analysis based on a phase 2, single-arm clinical trial and multicohort was performed from June 25 through September 30, 2019. Data are from the phase 2 IMvigor210 trial and from The Cancer Genome Atlas (TCGA). The study analyzed lncRNA and genomic data of 348 patients with bladder cancer from the IMvigor210 trial and 71 patients with melanoma from TCGA who were treated with immunotherapy. In addition, a pancancer multicohort that included 2951 patients was obtained from TCGA. Main Outcomes and Measures:The primary end point was overall survival (OS). Results:Among 348 patients from the IMvigor210 trial (272 [78.2%] male) and 71 patients with melanoma from TCGA (mean [SD] age, 58.3 [13.4] years; 37 [52.1%] female), 4 distinct classes with statistically significant differences in OS (median months, not reached vs 9.6 vs 8.1 vs 6.7 months; P = .002) were identified. The greatest OS benefit was obtained in the immune-active class, as characterized by the immune-functional lncRNA signature and high CTL infiltration. Patients with low vs high lncRNA scores had statistically significantly longer OS (hazard ratio, 0.32; 95% CI, 0.24-0.42; P < .001) in the IMvigor210 trial and across various cancer types. The lncRNA score was associated with immunotherapeutic OS benefit in the IMvigor210 trial cohort (area under the curve [AUC], 0.79 at 12 months and 0.77 at 20 months) and in TCGA melanoma cohort (AUC, 0.87 at 24 months), superior tumor alteration burden, programmed cell death ligand 1 (PD-L1) expression, and cytotoxic T-lymphocyte (CTL) infiltration. Addition of the lncRNA score to the combination of tumor alteration burden, PD-L1 expression, and CTL infiltration to build a novel multiomics algorithm correlated more strongly with OS in the IMvigor210 trial cohort (AUC, 0.81 at 12 months and 0.80 at 20 months). Conclusions and Relevance:This study identifies novel lncRNA-based immune classes in cancer immunotherapy and recommends immunotherapy for patients in the immune-active class. In addition, the study recommends that the lncRNA score should be integrated into multiomic panels for precision immunotherapy.
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