scholarly journals Comprehensive Analysis of N6-methyladenosine Modification Patterns Associated With Multiomic Characteristics of Bladder Cancer

2021 ◽  
Vol 8 ◽  
Author(s):  
Jingchao Liu ◽  
Jianlong Wang ◽  
Meng Wu ◽  
Wei Zhang ◽  
Lingfeng Meng ◽  
...  
Keyword(s):  
Bladder Tumor ◽  
Drug Sensitivity ◽  
Immune Cell ◽  
Principal Component ◽  
Therapeutic Effects ◽  
Individual Sample ◽  
Bladder Tumors ◽  
Systematic Analysis ◽  
Tumor Mutation Burden ◽  
Mutation Burden

Purpose: To comprehensively analyze N6-methyladenosine modification patterns in bladder tumors and to further systematically explore the inherent relationships between these modification patterns and multiomic tumor characteristics.Materials and Methods: A total of 901 bladder tumor samples, including 405 samples from TCGA database, 188 samples from GSE13507 and 308 samples from GSE32894, were included in this systematic analysis. The N6-methyladenosine modification patterns were identified utilizing unsupervised clustering analysis. To quantify N6-methyladenosine modification patterns, the m6Ascore of individual sample was developed using principal component analysis algorithms. Relationships among immune infiltration, tumor mutation burden, various clinical characteristics, molecular subtypes, and the m6Ascore were systematically analyzed. The guiding value of m6Ascore in immunotherapy was further validated in an external trial cohort. Genomics of Drug Sensitivity in Cancer expression references were also utilized to perform drug sensitivity analysis for patients with distinct m6A modification patterns.Results: We determined three different N6-methyladenosine modification patterns for 901 bladder tumors. The quantitative m6Ascore of individual sample derived from N6-methyladenosine modification patterns could play a significant role in predicting overall survival, immune cell infiltration, and classic oncogene mutations. A low m6Ascore combined with high tumor mutation burden indicated better survival outcomes (p < 0.001). A higher m6Ascore also indicated a higher grade, higher T and N stage, elder ages, higher death rate, and higher PD1/PDL1/CTLA4 expressions (p < 0.01). The Basal type tended to exhibit significantly higher m6Ascores than the Luminal and Neuronal subtypes. External immunotherapy cohorts demonstrated that no difference in therapeutic effects was noted between the high and low m6Ascore groups when anti-PD1 immunotherapy was exclusively administered. When anti-PD1 and anti-CTLA4 immunotherapy were simultaneously administered, the high m6Ascore group had a significantly better prognosis than the low m6Ascore group (p < 0.001). High m6A groups were potentially sensitive to various medical treatments including Bleomycin, Bortezomib, Cisplatin, Cyclopamine, Dasatinib, Docetaxe, Rapamycin, and Vinblastine in this study.Conclusions: This study systematically revealed the important roles of m6A methylation modification patterns in bladder tumors. Detailed quantification of m6A modification patterns could improve our understanding of the bladder tumor microenvironments and could provide guidance for future immunotherapy strategies.

scholarly journals Characterization of the Immune Cell Infiltration Landscape of Thyroid Cancer for Improved Immunotherapy

2021 ◽  
Vol 8 ◽  
Author(s):  
Jing Gong ◽  
Bo Jin ◽  
Liang Shang ◽  
Ning Liu
Keyword(s):  
Thyroid Cancer ◽  
Immune Cell ◽  
Endocrine System ◽  
Principal Component ◽  
Prognostic Indicator ◽  
Cell Infiltration ◽  
Therapeutic Effects ◽  
Immune Cell Infiltration ◽  
Mutation Burden

Within the endocrine system, thyroid cancer (THCA) is the most typical malignant tumor. Tumor-infiltrating immune cells play vital roles in tumor progression, recurrence, metastasis as well as response to immunotherapy. However, THCA’s immune infiltrative landscape is still not clarified. Therefore, we utilized two statistical algorithms to investigate the immune cell infiltration (ICI) landscape of 505 THCA samples and defined three ICI immune subtypes. The ICI scores were calculated using principal-component analysis. Increased tumor mutation burden (TMB) and immune-related signaling pathways were associated to a high ICI score. The high ICI score group indicated a relatively longer overall survival (OS) than the low ICI score group. Most immune checkpoint-related and immune activation-related genes were considerably upregulated in the ICI high group, which indicates stronger immunogenicity and a greater likelihood of benefiting from immunotherapy. In two cohort studies of patients receiving immunotherapy, high-ICI-score group showed notable therapeutic effects and clinical advantages compared to those with lower ICI scores. These results demonstrate that ICI score acts as an effective prognostic indicator and predictor of response to immunotherapy.

scholarly journals Characterization of the Different Subtypes of Immune Cells Infiltration to Aid Immunotherapy

2021 ◽  
Author(s):  
Zhenqing Li ◽  
Kai Mao ◽  
Qun Xue
Keyword(s):  
Cell Proliferation ◽  
Lung Adenocarcinoma ◽  
Signaling Pathways ◽  
Immune Cell ◽  
Principal Component ◽  
Tumor Rejection ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Remission Rates

Abstract Backgroup：PD-1 ablation or PD-L1 specific monoclonal antibody (mAb) against PD-1 can recruit the accumulation of functional T cells, leading to tumor rejection in microenvironment and significantly improving the prognosis of various cancers. Despite these unprecedented clinical successes, intervention remission rates remain low after treatment, rarely exceeding 40%. The observation of PD-1/L1 blocking in patients is undoubtedly multifactorial, but the infiltrating degree of CD8+T cell may be an important factor for immunotherapeutic resistance.Method: We proposed two computational algorithms to reveal the immune cell infiltration (ICI) landscape of 1646 lung adenocarcinoma patients. Three ICI patterns were defined and the relative ICI scoring were depended on principal-component analysis.Result: A high ICI score was associated with the increased tumor mutation burden (TMB) and cell proliferation-related signaling pathways. Different cellular signaling pathways were observed in low ICI score subtypes, indicating cell proliferation active, and may be associated with poor prognosis. Conclusion: Our research identified that the ICI scores worked as an effective immunotherapy index, which may provide a promising therapeutic strategies on immune therapeutic for lung adenocarcinoma.

scholarly journals Association Between Tumor Mutation Burden and Prognosis in Lower-Grade Glioma: An Exploratory Study 

2021 ◽  
Author(s):  
Di Cao ◽  
Jun Wang ◽  
Yan Lin ◽  
Guangwei Li
Keyword(s):  
Immune Cell ◽  
Differential Expression Analysis ◽  
Cell Infiltration ◽  
Lower Grade ◽  
Immune Cell Infiltration ◽  
Hub Genes ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Lower Grade Glioma ◽  
Genome Atlas

Abstract Background: The therapeutic efficacy of immune checkpoint inhibitor therapy is highly influenced by tumor mutation burden (TMB). The relationship between TMB and prognosis in lower-grade glioma is still unclear. We aimed to explore the relationships and mechanisms between them in lower-grade glioma.Methods: We leveraged somatic mutation data from The Cancer Genome Atlas (TCGA). Clinical cases were divided into high- and low-TMB groups based on the median of TMB. Infiltrating immune cells were analyzed using CIBERSORT and differential expression analysis between the prognostic groups performed. The key genes were identified as intersecting between immune-related genes. Cox regression and survival analysis were performed on the intersecting genes. A total of 7 hub genes were identified. The effect of somatic copy number alterations (SCNA) of the hub genes on immune cell infiltration was analyzed using TIMER, which was used to determine the risk factors and immune infiltration status in LGG. Subsequently, based on hub genes, a TMB Prognosis Index (TMBPI) model was constructed to predict the risk in LGG patients. Besides, this model was validated using data from TCGA and Chinese Glioma Genome Atlas (CGGA).Results: High-TMB favored worse prognosis (P＜0.001) and macrophage infiltration was an independent risk factor (P＜0.001). In the high-TMB group (P=0.033, P=0.009), the proportion of macrophages M0 and M2 increased and monocytes decreased (P=0.006). Besides, the SCNA of the hub genes affected the level of immune cell infiltration by varying degrees among which IGF2BP3, NPNT, and PLA2G2A had a significant impact. The AUC of the ROC curve at 1-, 3- and 5-years were all above 0.74.Conclusions: This study implies that high-TMB correlated with unfavorable prognosis in lower-grade glioma. And high-TMB may have an impact on prognosis by changing tumor microenvironment, caused by the SCNAs of genes. The TMBPI model accurately predicted prognosis in LGG patients.

Systems Understanding of Synergism Between As4S4 and Imatinib in Treating BCR/ABL Leukemia Model and in Attenuating BCR/ABL Oncoprotein as Well as Related Regulatory Networks

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4234-4234
Author(s):  
Qun-Ye Zhang ◽  
Jian-Hua Mao ◽  
Ping Liu ◽  
Qiu-Hua Huang ◽  
Jing Lu ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Dynamic Change ◽  
Principal Component ◽  
K562 Cells ◽  
Therapeutic Effects ◽  
Imatinib Treatment ◽  
Ancient Medicine ◽  
Systematic Analysis ◽  
Biochemical Basis

Abstract The combination of Imatinib and arsenic sulfide (As4S4) exerts more profound in vivo therapeutic effects on chronic myeloid leukemia (CML) at both organism and cellular levels, as evident for the first time in this paper by significantly prolonged lifespan in mouse leukemia model bearing BCR/ABL and induction of apoptosis of BCR/ABL expressing cells. To address mechanisms underlying this synergy, we performed systematic analysis of the dynamic change of proteome, phosphoproteome and transcriptome in K562 cells after As4S4 and/or Imatinib treatment with the support of principal component analysis (PCA) and self-organization maps (SOM). Moreover, protein biochemistry experiments were performed to confirm the important conclusions from multiomics study. The integrated information indicated that As4S4 promoted the unfolding protein reaction (UPR) and activity of ubiquitination pathway, which can be considered as a major biochemical basis of the pharmacological effects of this ancient medicine. In this context, As4S4 was shown to target BCR/ABL through ubiquitination of key lysine residues and led subsequently to its degradation by proteasome. Meanwhile, Imatinib inhibited the PI3K/AKT/mTOR pathway with synergism of As4S4 and arrested cell cycle. Combination of the two agents synergistically decreased activity and quantity of BCR/ABL and activated intrinsic and extrinsic apoptosis pathways. These complex multi-molecular target and multi-pathway modifications at protein level, together with those at transcriptional regulation level, ultimately resulted in the synergistic attenuation of BCR/ABL oncoprotein and the therapeutic effects on CML model.

scholarly journals Molecular Characterization of the Clinical and Tumor Immune Microenvironment Signature of 5-methylcytosine-Related Regulators in non-small Cell Lung Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Taisheng Liu ◽  
Liyi Guo ◽  
Guihong Liu ◽  
Xiaoshan Hu ◽  
Xiaoning Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Microenvironment ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Check Point ◽  
Clinical Prognosis ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Immune Check Point Inhibitor

Background: DNA methylation is an important epigenetic modification, among which 5-methylcytosine methylation (5mC) is generally associated with tumorigenesis. Nonetheless, the potential roles of 5mC regulators in the tumor microenvironment (TME) remain unclear.Methods: The 5mC modification patterns of 1,374 lung adenocarcinoma samples were analyzed systematically. The correlation between the 5mC modification and tumor microenvironment cell infiltration was further assessed. The 5mCscore was developed to evaluate tumor mutation burden, immune check-point inhibitor response, and the clinical prognosis of individual tumors.Results: Three 5mC modification patterns were established based on the clinical characteristics of 21 5mC regulators. According to the differential expression of 5mC regulators, three distinct 5mC gene cluster were also identified, which showed distinct TME immune cell infiltration patterns and clinical prognoses. The 5mCscore was constructed to evaluate the tumor mutation burden, immune check-point inhibitor response, and prognosis characteristics. We found that patients with a low 5mCscore had significant immune cell infiltration and increased clinical benefit.Conclusion: This study indicated that the 5mC modification is involved in regulating TME infiltration remodeling. Targeting 5mC modification regulators might be a novel strategy to treat lung cancer.

scholarly journals Histone Methylation Modification Patterns and Relevant M-RiskScore in Acute Myeloid Leukemia

2021 ◽  
Author(s):  
Dade Rong ◽  
Xiaomin Chen ◽  
Daiyuan Liu ◽  
Xiangna Ni ◽  
Zhuomao Mo ◽  
...  
Keyword(s):  
Histone Methylation ◽  
Scoring System ◽  
Myeloid Leukemia ◽  
Somatic Mutations ◽  
Immune Cell ◽  
Molecular Subtypes ◽  
Immune Cell Infiltration ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Acute Myeloid

Abstract Background: Acute myeloid leukemia (AML) is a type of heterogeneous disease with varied prognosis, but current classification methods for AML do not play an ideal role in guiding the therapy. Emerging studies shown alteration of histone methylation is closely related to leukemogenesis. This study aimed at identifying the molecular subtypes associated with histone methylation and establishing a relevant score to predict treatment respond and prognosis in AML.Methods: Gene expression data and clinical characteristics of patients with AML were obtained from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database. Molecular subtypes were identified by consensus clustering based on the expression of 24 histone methylation modification regulators (HMMRs). The clinical and biological features of each pattern were investigated by unsupervised clustering, survival, principle component (PCA), somatic mutations, gene set variation (GSVA), tumor mutation burden (TMB) and immune cell infiltration analyses. Different expression analysis and lasso regression analysis was conducted to establish the scoring system that was explored in the role of prognosis by using receivers operating curve (ROC) analysis and univariate/multivariate Cox regression analyses. Moreover, correlation analysis was performed to investigate the value of scoring system in chemotherapeutic prediction. Finally, an independent GSE dataset was used as a reference to validate the established clustering system.Results: Two distinct histone methylation modification patterns had been identified that exhibit remarkable differences in several clinical and biological characteristics, including HMMRs’ expression, AML-M0 distribution, mutations of NPM1, survival, tumor mutation burden, somatic mutations, pathways activation and immune cell infiltration. Besides, based on the clustering, we established the scoring system, M-RiskScore. Integrated analysis demonstrated that M-RiskScore-low patients displayed a prominent survival advantage and a better respond to decitabine treatment, while the opposite site was reported to M-RiskScore-high patients but they could benefit more from IA regimen therapy.Conclusion: Our results demonstrate that detection of HMMRs’ expression is potentially useful to AML therapy decisions, and targeting histone methylation would be a more promising strategy for either AML-M0 or NPM1 mutant patients. M-RiskScore is a hopeful independent poor prognostic biomarker and be able to benefits the treatment decisions in AML.

scholarly journals The Adaptive Immune Landscape of the Colorectal Adenoma–Carcinoma Sequence

2021 ◽  
Vol 22 (18) ◽  
pp. 9791
Author(s):  
João Augusto Freitas ◽  
Irene Gullo ◽  
Diogo Garcia ◽  
Sara Miranda ◽  
Louisa Spaans ◽  
...  
Keyword(s):  
Colorectal Adenoma ◽  
Immune Cell ◽  
Low Grade ◽  
Mhc I ◽  
Tumor Mutation Burden ◽  
Adaptive Immune ◽  
Cell Counts ◽  
Mutation Burden ◽  
Tumor Immune Microenvironment ◽  
Immunosuppressive Tumor Microenvironment

Background. The tumor immune microenvironment exerts a pivotal influence in tumor initiation and progression. The aim of this study was to analyze the immune context of sporadic and familial adenomatous polyposis (FAP) lesions along the colorectal adenoma–carcinoma sequence (ACS). Methods. We analyzed immune cell counts (CD3+, CD4+, CD8+, Foxp3+, and CD57+), tumor mutation burden (TMB), MHC-I expression and PD-L1 expression of 59 FAP and 74 sporadic colorectal lesions, encompassing adenomas with low-grade dysplasia (LGD) (30 FAP; 30 sporadic), adenomas with high-grade dysplasia (22 FAP; 30 sporadic), and invasive adenocarcinomas (7 FAP; 14 sporadic). Results. The sporadic colorectal ACS was characterized by (1) a stepwise decrease in immune cell counts, (2) an increase in TMB and MHC-I expression, and (3) a lower PD-L1 expression. In FAP lesions, we observed the same patterns, except for an increase in TMB along the ACS. FAP LGD lesions harbored lower Foxp3+ T cell counts than sporadic LGD lesions. A decrease in PD-L1 expression occurred earlier in FAP lesions compared to sporadic ones. Conclusions. The colorectal ACS is characterized by a progressive loss of adaptive immune infiltrate and by the establishment of a progressively immune cold microenvironment. These changes do not appear to be related with the loss of immunogenicity of tumor cells, or to the onset of an immunosuppressive tumor microenvironment.

Tumor mutation burden and immune microenvironment analysis of urothelial carcinoma.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 494-494
Author(s):  
Yuanyuan Jia ◽  
Ning He ◽  
Yadong Yang ◽  
Yuliang Huang ◽  
Xiaoyu Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Urothelial Carcinoma ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Immune Therapy ◽  
Genetic Alterations ◽  
Rank Test ◽  
Immune Microenvironment ◽  
Tumor Mutation Burden ◽  
Mutation Burden

494 Background: Tumor mutation burden (TMB) has been established as a biomarker for response to immune therapy and prognosis in various cancers. However, the correlation between TMB and immune microenvironment remains unwell studied, especially in urothelial carcinoma. This study was aimed to investigate the relationship between TMB and other immunotherapy related biomarkers, including genetic alterations, APOBEC signature, microsatellite instability (MSI), PD-L1 expression and immune cell infiltration in urothelial carcinoma. Methods: 131 patients with urothelial carcinoma admitted from October 2018 to May 2020 were included. Total DNA was isolated from FFPE or fresh tissues. Mutation profiles, APOBEC signature and MSI scores were obtained by next-generation sequencing based a 642 cancer genes panel assay. PD-L1 expression, CD8+ T-cells and tumor-infiltrating lymphocytes density were evaluated by immunohistochemistry. The correlation was analyzed by Wilcoxon signed-rank test. Results: The mutation landscape showed that TP53 mutation is the most common alterations (n = 64/131, 48.9%), followed by KMT2D alterations (n = 49/131, 37.4%), KDM6A mutations (n = 42/131, 32.1%), MUC17 mutations (n = 42/131, 32.1%). The median TMB was 5.06 Muts/Mb (0-118 Muts/Mb). 2 of 131 patients showed MSI-H, who exhibited a much higher TMB (41, 118 Muts/Mb). Further analysis showed that TMB in the patients with certain gene mutations (such as TP53, KMT2D, KDM6A and MUC17) was significantly higher than those wild type ones (p < 0.05). Meanwhile, the high APOBEC-enrichment group has a higher TMB than the low APOBEC-enrichment group (p = 0.045). Furthermore,we observed that the patients with a higher PD-L1 expression (n = 28/131, 21.4%, at a combined positive score cut-off value of 10) also showed a significantly higher TMB (p = 0.016), and TMB in the patients with higher density of CD8+ T-cells (n = 42/131, 32.1%, at a cut-off value of 5%) was also significantly higher than that of the group with lower density of CD8+ T-cells (p = 0.039). Conclusions: This study provides new insights into the correlation between the TMB and the immune microenvironment in urothelial carcinoma. The result may be a reference to immunotherapy.

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