Identifying GNG4 might play an important role in colorectal cancer TMB

2021 ◽  
pp. 1-16
Author(s):  
Hongcan Zhao ◽  
Sheng Danli ◽  
Ze Qian ◽  
Sunyi Ye ◽  
Jianzhong Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastases ◽  
Genomic Analysis ◽  
Recurrence Risk ◽  
Computational Method ◽  
The Cancer Genome Atlas ◽  
Immune Microenvironment ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Tumor Immune Microenvironment

BACKGROUND: Colorectal carcinoma (CRC) is one of the most leading cause of cancer death all over the world. The tumor immune microenvironment is illustrated to be necessary for the progress of CRC. And the accumulating evidence indicated that tumor mutation burden (TMB) is effective in differentiating responding population of immune checkpoint inhibitor (ICI) therapies in various cancers. In this study, we aimed to evaluated the potential relationship between TMB and the recurrence risk of CRC. METHODS: The transcriptomic and clinical data of CRC patients were collected from The Cancer Genome Atlas (TCGA) database (n= 382). Then the genomic analysis of tumor mutation burden and tumor purity were conducted by a computational method based on transcriptomic data. RESULTS: Firstly, we accessed the distribution of TMB and preferences at the gene and mutation level using somatic mutation data from TCGA data about CRC. We identified that high TMB predicted better prognosis of CRC patients. Secondly, the differentially expressed genes (DEGs) between the low TMB and high TMB group was clarified. Then the protein-protein interaction (PPI) analysis was performed, and the results confirmed ten hub genes among the DEGs. Utilizing the GEPIA web-tool, we discovered that GNG4 was up-regulated in tumor tissues, and GNG4 was related to the overall survival (OS) and tumor free survival (TFS) of CRC patients. Therefore, we considered GNG4 was essential for the tumor immune microenvironment of CRC. Furthermore, we also accessed the protein level of GNG4 in CRC and liver metastases from CRC. CONCLUSIONS: In this study, GNG4 was demonstrated to be the key element of the CRC TMB, which will be essential for the ICI therapy of CRC. Besides, GNG4 was up-regulated in CRC and liver metastases from CRC tissues. Thus, we thought that GNG4 might play an important role in colorectal cancer TMB and induce its metastasis in liver.

scholarly journals Genomic features and tumor immune microenvironment alteration in NSCLC treated with neoadjuvant PD-1 blockade

2022 ◽  
Vol 6 (1) ◽  
Author(s):  
Shuhang Wang ◽  
Pei Yuan ◽  
Beibei Mao ◽  
Ning Li ◽  
Jianming Ying ◽  
...  
Keyword(s):  
Copy Number ◽  
Copy Number Gain ◽  
Pathological Response ◽  
Immune Microenvironment ◽  
Tumor Mutation Burden ◽  
Neoadjuvant Immunotherapy ◽  
Mutation Burden ◽  
Tumor Immune Microenvironment ◽  
Nsclc Patients ◽  
Insight Into

AbstractSeveral clinical trials have shown the safety and effectiveness of PD-1/PD-L1 inhibitors in neoadjuvant therapy in resectable non-small cell lung cancer (NSCLC). However, 18–83% patients can benefit from it. In this study, we aimed to assess the association of PD-L1 expression, tumor mutation burden, copy number alteration (CNA, including copy number gain and loss) burden with the pathologic response to neoadjuvant PD-1 blockade and investigate the changes in the tumor immune microenvironment (TIME) during neoadjuvant immunotherapy in NSCLC. Pre-immunotherapy treatment tumor samples from twenty-nine NSCLC patients who received neoadjuvant immunotherapy with sintilimab, an anti-PD-1 drug, were subjected to targeted DNA sequencing and PD-L1 immunochemistry staining. The pathological response was positively correlated with tumor proportion score (TPS) of PD-L1 and negatively correlated with copy number gain (CNgain) burden. Of note, the combination of CNgain burden and TPS can better stratify major pathological response (MPR) patients than did CNgain or TPS alone. Whereas, TMB showed a limited correlation with pathological regression. Additionally, PD-1 blockade led to an increase in CD8+PD-1−T cells which was clinically relevant to MPR as evaluated by multiplex immunofluorescence. A significant reduction in CD19+ cells was observed in the Non-MPR group but not in the MPR group, indicating the involvement of B cells in improving neoadjuvant immunotherapy response in NSCLC. Together, our study provides new data for the correlation of PD-L1 expression and genomic factors with drug response in neoadjuvant immunotherapy settings in NSCLC. The changes of TIME may provide novel insight into the immune responses to neoadjuvant anti-PD-1 therapy.

scholarly journals MUC4 mutation correlates with tumor mutation burden and the immune microenvironment in colorectal cancer

2020 ◽  
Author(s):  
Ting Li ◽  
Wenjia Hui ◽  
Halina Halike ◽  
Feng Gao
Keyword(s):  
Colorectal Cancer ◽  
Immune Response ◽  
T Cells ◽  
Immune Cells ◽  
Gene Mutations ◽  
Cancer Genome ◽  
Immune Microenvironment ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Mutant Genes

Abstract Background: Immunotherapy is a new strategy for Colorectal cancer (CRC) treatment. Tumor mutation burden (TMB) may act as an emerging biomarker for predicting responses to immunotherapy. Nevertheless, no studies investigate if these gene mutations correlate to TMB and tumor-infiltrating immune cells. Methods: Somatic mutation data for CRC samples were obtained from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) datasets. Then, we investigated the relationship between these mutant genes, TMB and overall survival outcomes. GSEA analysis was performed to explore the underlying mechanism of mutant gene. Finally, we further verified the connection between gene mutations and immune response.Results: We identified 17 common mutant genes shared by both two cohorts. Further analysis found that MUC4 mutation was strongly related to higher TMB and predicted a poorer prognosis. Moreover, functional enrichment analysis of samples with MUC4 mutation revealed that they were involved in regulating the natural killer cell mediated cytotoxicity signaling pathway. Significant changes in the proportion of the immune cells of CD8 T cells, activated NK cells, M1 macrophages and resting memory CD4 T cells were observed using the CIBERSORT algorithm. Conclusions: Our research revealed that MUC4 mutation significantly correlated with increased TMB, a worse prognosis and modulating the immune microenvironment, which may be considered a biomarker to predict the outcome of the immune response in colorectal cancer.

scholarly journals Constructing Tumor Immune Microenvironment and Identifying the Immune-Related Prognostic Signatures in Colorectal Cancer Using Multi-omics Data

2021 ◽  
Author(s):  
Shuai Zhang ◽  
Jiali Lv ◽  
Bingbing Fan ◽  
Zhe Fan ◽  
Chunxia Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cross Validation ◽  
Cox Regression ◽  
Risk Group ◽  
The Cancer Genome Atlas ◽  
Omics Data ◽  
Epigenetic Alterations ◽  
Lasso Regression ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment

ABSTRACTBackgroundThe tumor immune microenvironment (TIME) plays a key role in occurrence, progression and prognosis of colorectal cancer (CRC). However, the genetic and epigenetic alterations and potential mechanisms in the TIME of CRC are still unclear.MethodsWe investigated the immune-related differences in three types of genetic or epigenetic alterations (gene expression, somatic mutation, and DNA methylation) and considered the potential roles that these alterations have in the immune response and the immune-related biological processes by analyzing the multi-omics data from The Cancer Genome Atlas (TCGA) portal. Additionally, a four-step method based on LASSO regression and Cox regression was used to construct the prognostic prediction model. Cross validation was performed to validate the model.ResultsA total of 1,745 differentially expressed genes, 178 differentially mutated genes and 1,961 differentially methylation probes were identified between the high-immunity group and the low-immunity group. We retained 15 genetic and epigenetic variables after using LASSO regression and Cox regression. For the prognostic predictions on the TCGA profiles, the performance of the model with 1-year, 3-year, and 5-year areas under the curve (AUCs) equal to 0.861, 0.797, and 0.875. Finally, the overall risk score model was constructed based on genetic, epigenetic, demographic and clinical characteristics, which comprised 18 variables and achieved a high degree of accuracy on the 1-year (AUC = 0.865), 3-year (AUC = 0.839), and 5-year (AUC = 0.914) survival predictions. Kaplan-Meier survival analysis demonstrated that the overall survival of the high-risk group was significantly poorer compared with the low-risk group. Prognostic nomogram, calibration plot and cross validation showed excellent predictive performance.ConclusionsOur study provides a new clue to explore the TIME of CRC patients in genetic and epigenetic aspects. Meanwhile, the prognostic model also has clinical prognostic value and may provide new indicators for the treatment of CRC patients.

scholarly journals Role of tumor mutation burden-related signatures in the prognosis and immune microenvironment of pancreatic ductal adenocarcinoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Rong Tang ◽  
Xiaomeng Liu ◽  
Wei Wang ◽  
Jie Hua ◽  
Jin Xu ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Predictive Accuracy ◽  
The Cancer Genome Atlas ◽  
Ductal Adenocarcinoma ◽  
Immune Microenvironment ◽  
Tumor Mutation Burden ◽  
Oncogenic Pathways ◽  
Mutation Burden ◽  
Cancer Genome Atlas

Abstract Background High tumor mutation burden (TMB) has gradually become a sensitive biomarker for predicting the response to immunotherapy in many cancers, including lung, bladder and head and neck cancers. However, whether high TMB predicts the response to immunotherapy and prognosis in pancreatic ductal adenocarcinoma (PDAC) remained obscure. Hence, it is significant to investigate the role of genes related to TMB (TRGs) in PDAC. Methods The transcriptome and mutation data of PDAC was downloaded from The Cancer Genome Atlas-Pancreatic Adenocarcinoma (TCGA). Five independent external datasets of PDAC were chosen to validate parts of our results. qRT-PCR and immunohistochemical staining were also performed to promote the reliability of this study. Results The median overall survival (OS) was significantly increased in TMB_low group compared with the counterpart with higher TMB score after tumor purity adjusted (P = 0.03). 718 differentially expressed TRGs were identified and functionally enriched in some oncogenic pathways. 67 TRGs were associated with OS in PDAC. A prognostic model for the OS was constructed and showed a high predictive accuracy (AUC = 0.849). We also found TMB score was associated with multiple immune components and signatures in tumor microenvironment. In addition, we identified a PDAC subgroup featured with TMBlowMicrosatellite instabilityhigh (MSIhigh) was associated with prolonged OS and a key molecule, ANKRD55, potentially mediating the survival benefits. Conclusion This study analyzed the biological function, prognosis value, implications for mutation landscape and potential influence on immune microenvironment of TRGs in PDAC, which contributed to get aware of the role of TMB in PDAC. Future studies are expected to investigate how these TRGs regulate the initiation, development or repression of PDAC.

scholarly journals Tumor Immune Microenvironment Landscape in Glioma Identifies a Prognostic and Immunotherapeutic Signature

2021 ◽  
Vol 9 ◽  
Author(s):  
Chunyu Zhang ◽  
Lirui Guo ◽  
Zhongzhou Su ◽  
Na Luo ◽  
Yinqiu Tan ◽  
...  
Keyword(s):  
Large Scale ◽  
The Cancer Genome Atlas ◽  
Immune Microenvironment ◽  
Mutation Burden ◽  
Tumor Immune Microenvironment ◽  
Cancer Genome Atlas ◽  
Patient Prognosis ◽  
Selection Operator ◽  
Cox Analysis ◽  
Genome Atlas

The tumor immune microenvironment (TIME) has been recognized to be associated with sensitivity to immunotherapy and patient prognosis. Recent research demonstrates that assessing the TIME patterns on large-scale samples will expand insights into TIME and will provide guidance to formulate immunotherapy strategies for tumors. However, until now, thorough research has not yet been reported on the immune infiltration landscape of glioma. Herein, the CIBERSORT algorithm was used to unveil the TIME landscape of 1,975 glioma observations. Three TIME subtypes were established, and the TIMEscore was calculated by least absolute shrinkage and selection operator (LASSO)–Cox analysis. The high TIMEscore was distinguished by an elevated tumor mutation burden (TMB) and activation of immune-related biological process, such as IL6-JAK-STAT3 signaling and interferon gamma (IFN-γ) response, which may demonstrate that the patients with high TIMEscore were more sensitive to immunotherapy. Multivariate analysis revealed that the TIMEscore could strongly and independently predict the prognosis of gliomas [Chinese Glioma Genome Atlas (CGGA) cohort: hazard ratio (HR): 2.134, p < 0.001; Gravendeel cohort: HR: 1.872, p < 0.001; Kamoun cohort: HR: 1.705, p < 0.001; The Cancer Genome Atlas (TCGA) cohort: HR: 2.033, p < 0.001; the combined cohort: HR: 1.626, p < 0.001], and survival advantage was evident among those who received chemotherapy. Finally, we validated the performance of the signature in human tissues from Wuhan University (WHU) dataset (HR: 15.090, p = 0.008). Our research suggested that the TIMEscore could be applied as an effective predictor for adjuvant therapy and prognosis assessment.

scholarly journals A next-generation sequencing-based strategy combining microsatellite instability and tumor mutation burden for comprehensive molecular diagnosis of advanced colorectal cancer

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jian Xiao ◽  
Wenyun Li ◽  
Yan Huang ◽  
Mengli Huang ◽  
Shanshan Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Molecular Diagnosis ◽  
Checkpoint Inhibitors ◽  
The Cancer Genome Atlas ◽  
Immune Microenvironment ◽  
Mutational Burden ◽  
Immune Signatures ◽  
Mutation Burden ◽  
Tumor Mutational Burden

Abstract Background Mismatch repair (MMR)/microsatellite instability (MSI) and tumor mutational burden (TMB) are independent biomarkers that complement each other for predicting immune checkpoint inhibitors (ICIs) efficacy. Here we aim to establish a strategy that integrates MSI and TMB determination for colorectal cancer (CRC) in one single assay. Methods Surgical or biopsy specimens retrospectively collected from CRC patients were subjected to NGS analysis. Immunohistochemistry (IHC) and polymerase chain reaction (PCR) were also used to determine MMR/MSI for those having enough tissues. The NGS-MSI method was validated against IHC and PCR. The MSI-high (MSI-H) or microsatellite stable (MSS) groups were further stratified based on tumor mutational burden, followed by validation using the The Cancer Genome Atlas (TCGA) CRC dataset. Immune microenvironment was evaluated for each subgroup be profiling the expression of immune signatures. Results Tissues from 430 CRC patients were analyzed using a 381-gene NGS panel. Alterations in KRAS, NRAS, BRAF, and HER2 occurred at a significantly higher incidence among MSI-H tumors than in MSS patients (83.6% vs. 58.4%, p = 0.0003). A subset comprising 98 tumors were tested for MSI/MMR using all three techniques, where NGS proved to be 99.0 and 93.9% concordant with PCR and IHC, respectively. Four of the 7 IHC-PCR discordant cases had low TMB (1.1–8.1 muts/Mb) and were confirmed to have been misdiagnosed by IHC. Intriguingly, 4 of the 66 MSS tumors (as determined by NGS) were defined as TMB-high (TMB-H) using a cut-off of 29 mut/Mb. Likewise, 15 of the 456 MSS tumors in the TCGA CRC cohort were also TMB-H with a cut-off of 9 muts/Mb. Expression of immune signatures across subgroups (MSS-TMB-H, MSI-H-TMB-H, and MSS-TMB-L) confirmed that the microenvironment of the MSS-TMB-H tumors was similar to that of the MSI-H-TMB-H tumors, but significantly more immune-responsive than that of the MSS-TMB-L tumors, indicating that MSI combined with TMB may be more precise than MSI alone for immune microenvironment prediction. Conclusion This study demonstrated that NGS panel-based method is both robust and tissue-efficient for comprehensive molecular diagnosis of CRC. It also underscores the importance of combining MSI and TMB information for discerning patients with different microenvironment.

scholarly journals A novel 10-gene immune-related lncRNA signature model for the prognosis of colorectal cancer

2021 ◽  
Vol 18 (6) ◽  
pp. 9743-9760
Author(s):  
Bin Ma ◽  
◽  
Lianqun Cao ◽  
Yongmin Li
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Clinical Stage ◽  
The Cancer Genome Atlas ◽  
Immune Checkpoints ◽  
Protein Networks ◽  
Immune Microenvironment ◽  
Carcinogenic Effect ◽  
Clinical Prognosis ◽  
Tumor Immune Microenvironment

<abstract> <sec><title>Background</title><p>The tumor immune microenvironment of colorectal cancer (CRC) affects tumor development, prognosis and immunotherapy strategies. Recently, immune-related lncRNA were shown to play vital roles in the tumor immune microenvironment. The objective of this study was to identify lncRNAs involved in the immune response, tumorigenesis and progression of CRC and to establish an immune-related lncRNA signature for predicting the prognosis of CRC.</p> </sec> <sec><title>Methods</title><p>We used data retrieved from the cancer genome atlas (TCGA) dataset to construct a 10-gene immune-related lncRNA pair (IRLP) signature model using a method based on the ranking and comparison of paired gene expression in CRC. The clinical prognosis, immune checkpoints and lncRNA-protein networks were analyzed to evaluate the signature.</p> </sec> <sec><title>Results</title><p>The signature was closely associated with overall survival of CRC patients (p &lt; 0.001 in both of the training and validating cohorts) and the 3-year AUC values for the training and validating cohorts were 0.884 and 0.739, respectively. And, there were positive correlations between the signature and age (p = 0.048), clinical stage (p &lt; 0.01), T stage (p &lt; 0.01), N stage (p &lt; 0.001) and M stage (p &lt; 0.01). In addition, the signature model appeared to be highly relevant to some checkpoints, including CD160, TNFSF15, HHLA2, IDO2 and KIR3DL1. Further, molecular functional analysis and lncRNA-protein networks were applied to understand the molecular mechanisms underlying the carcinogenic effect and progression.</p> </sec> <sec><title>Conclusion</title><p>The 10-gene IRLP signature model is an independent prognostic factor for CRC patient and can be utilized for the development of immunotherapy.</p> </sec> </abstract>

scholarly journals Role of Tumor Mutation Burden-related Signatures in the Prognosis and Immune Microenvironment of Pancreatic Ductal Adenocarcinoma

2021 ◽  
Author(s):  
Rong Tang ◽  
Xiaomeng Liu ◽  
Wei Wang ◽  
Jie Hua ◽  
Jin Xu ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Predictive Accuracy ◽  
The Cancer Genome Atlas ◽  
Ductal Adenocarcinoma ◽  
Immune Microenvironment ◽  
Tumor Mutation Burden ◽  
Oncogenic Pathways ◽  
Mutation Burden ◽  
Cancer Genome Atlas

Abstract Background High tumor mutation burden (TMB) has gradually become a sensitive biomarker for predicting the response to immunotherapy in many cancers, including lung, bladder and head and neck cancers. Nonetheless, whether high TMB could predict the response to immunotherapy and prognosis in pancreatic ductal adenocarcinoma (PDAC), a classic “cold” tumor, remained obscure. Hence, it is significant to investigate the role of genes related to TMB (TRGs) in PDAC.Methods The transcriptome and mutation data of PDAC was downloaded from The Cancer Genome Atlas-Pancreatic Adenocarcinoma (TCGA). Five independent external datasets of PDAC were chosen to validate parts of our results. qRT-PCR and immunohistochemical staining were also performed to promote the reliability of this study. Results The median overall survival (OS) was significantly increased in TMB_low group compared with the counterpart with higher TMB score after tumor purity adjusted (P = 0.03). 718 differentially expressed TRGs were identified and functionally enriched in some oncogenic pathways. 67 TRGs were associated with OS in PDAC. A prognostic model for the OS was constructed and showed a high predictive accuracy (AUC = 0.849). We also found TMB score was associated with multiple immune components and signatures in tumor microenvironment. In addition, we identified a PDAC subgroup featured with TMBlowMSIhigh was associated with prolonged OS and a key molecule, ANKRD55, potentially mediating the survival benefits.Conclusion This study analyzed the biological function, prognosis value, implications for mutation landscape and potential influence on immune microenvironment of TRGs in PDAC, which contributed to get aware of the role of TMB in PDAC. Future studies are expected to investigate how these TRGs regulate the initiation, development or repression of PDAC.

scholarly journals Heparanase (HPSE) Associates with the Tumor Immune Microenvironment in Colorectal Cancer

Processes ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1605
Author(s):  
Mengling Liu ◽  
Qing Liu ◽  
Yitao Yuan ◽  
Suyao Li ◽  
Yu Dong ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Positive Association ◽  
Immune Microenvironment ◽  
High Expression Group ◽  
Mutation Burden ◽  
Tumor Immune Microenvironment ◽  
Public Datasets

There is an unmet clinical need to identify potential predictive biomarkers for immunotherapy efficacy in mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC). Heparanase (HPSE) is a multifunctional molecule mediating tumor–host crosstalk. However, the function of HPSE in the tumor immune microenvironment of CRC remains unclear. Data of CRC patients from public datasets (TCGA and GSE39582) and Zhongshan Hospital (ZS cohort) were collected to perform integrative bioinformatic analyses. In total, 1036 samples from TCGA (N = 457), GSE39582 (N = 510) and ZS cohort (N = 69) were included. Samples of deficient MMR (dMMR) and consensus molecular subtypes 1 (CMS1) showed significantly higher HPSE expression. The expression of HPSE also exhibited a significantly positive association with PD-L1 expression, tumor mutation burden and the infiltration of macrophages. Immune pathways were remarkably enriched in the HPSE high-expression group, which also showed higher expressions of chemokines and immune checkpoint genes. Survival analysis suggested that high HPSE expression tended to be associated with shorter overall survival in patients with pMMR mCRC. HPSE might contribute to the immune-activated tumor microenvironment with high levels of immune checkpoint molecules, suggesting that pMMR mCRC with high HPSE expression might respond to immune checkpoint inhibitors.

Sign in / Sign up

Export Citation Format

Share Document