Associating transcriptomics data with inflammatory markers to understand tumour microenvironment in hepatocellular carcinoma
Abstract Background Liver cancer is the fourth leading cause of cancer‐related death globally which is estimated to reach more than 1 million deaths a year by 2030. Among liver cancer types, hepatocellular carcinoma (HCC) accounts for approximately 90% of the cases and is known to have a tumour prom...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-01-01
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| Series: | Cancer Medicine |
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| Online Access: | https://doi.org/10.1002/cam4.4941 |
| _version_ | 1797950834521145344 |
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| author | Basak Bahcivanci Roshan Shafiha Georgios V. Gkoutos Animesh Acharjee |
| author_facet | Basak Bahcivanci Roshan Shafiha Georgios V. Gkoutos Animesh Acharjee |
| author_sort | Basak Bahcivanci |
| collection | DOAJ |
| description | Abstract Background Liver cancer is the fourth leading cause of cancer‐related death globally which is estimated to reach more than 1 million deaths a year by 2030. Among liver cancer types, hepatocellular carcinoma (HCC) accounts for approximately 90% of the cases and is known to have a tumour promoting inflammation regardless of its underlying aetiology. However, current promising treatment approaches, such as immunotherapy, are partially effective for most of the patients due to the immunosuppressive nature of the tumour microenvironment (TME). Therefore, there is an urgent need to fully understand TME in HCC and discover new immune markers to eliminate resistance to immunotherapy. Methods We analyse three microarray datasets, using unsupervised and supervised methods, in an effort to discover signature genes. First, univariate, and multivariate, feature selection methods, such as the Boruta algorithm, are applied. Subsequently, an optimisation procedure, which utilises random forest algorithm with three dataset pairs combinations, is performed. The resulting optimal gene sets are then combined and further subjected to network analysis and pathway enrichment analysis so as to obtain information related to their biological relevance. The microarray datasets were analysed via the MCP‐counter, CIBERSORT, TIMER, EPIC, and quanTIseq deconvolution methods and an estimation of cell type abundances for each dataset sample were identified. The differences in the cell type abundances, between the adjacent and tumour sample groups, were then assessed using a Wilcoxon Rank Sum test (p‐value < 0.05). Results The optimal gene signature sets, derived from each of the data pairs combination, achieved AUC values ranging from 0.959 to 0.988 in external validation sets using Random Forest model. CLEC1B and PTTG1 genes are retrieved across each optimal set. Among the signature genes, PTTG1, AURKA, and UBE2C genes are found to be involved in the regulation of mitotic sister chromatid separation and anaphase‐promoting complex (APC) dependent catabolic process (adjusted p‐value < 0.001). Additionally, the application of deconvolution algorithms revealed significant changes in cell type abundances of Regulatory T (Treg) cells, M0 and M1 macrophages, and T CD8+ cells between adjacent and tumour samples. Conclusion We identified ECM1 gene as a potential immune‐related marker acting through immune cell migration and macrophage polarisation. Our results indicate that macrophages, such as M0 macrophage and M1 macrophage cells, undergo significant changes in HCC TME. Moreover, our immune deconvolution approach revealed significant infiltration of Treg cells and M0 macrophages, and a significant decrease in T CD8+ cells and M1 macrophages in tumour samples. |
| first_indexed | 2024-04-10T22:22:24Z |
| format | Article |
| id | doaj.art-d44cf514e1fc48fab6ee70707453475c |
| institution | Directory Open Access Journal |
| issn | 2045-7634 |
| language | English |
| last_indexed | 2024-04-10T22:22:24Z |
| publishDate | 2023-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj.art-d44cf514e1fc48fab6ee70707453475c2023-01-17T17:10:25ZengWileyCancer Medicine2045-76342023-01-0112169671110.1002/cam4.4941Associating transcriptomics data with inflammatory markers to understand tumour microenvironment in hepatocellular carcinomaBasak Bahcivanci0Roshan Shafiha1Georgios V. Gkoutos2Animesh Acharjee3College of Medical and Dental Sciences, Institute of Cancer and Genomic Sciences, Centre for Computational Biology University of Birmingham Birmingham UKCollege of Medical and Dental Sciences, Institute of Cancer and Genomic Sciences, Centre for Computational Biology University of Birmingham Birmingham UKCollege of Medical and Dental Sciences, Institute of Cancer and Genomic Sciences, Centre for Computational Biology University of Birmingham Birmingham UKCollege of Medical and Dental Sciences, Institute of Cancer and Genomic Sciences, Centre for Computational Biology University of Birmingham Birmingham UKAbstract Background Liver cancer is the fourth leading cause of cancer‐related death globally which is estimated to reach more than 1 million deaths a year by 2030. Among liver cancer types, hepatocellular carcinoma (HCC) accounts for approximately 90% of the cases and is known to have a tumour promoting inflammation regardless of its underlying aetiology. However, current promising treatment approaches, such as immunotherapy, are partially effective for most of the patients due to the immunosuppressive nature of the tumour microenvironment (TME). Therefore, there is an urgent need to fully understand TME in HCC and discover new immune markers to eliminate resistance to immunotherapy. Methods We analyse three microarray datasets, using unsupervised and supervised methods, in an effort to discover signature genes. First, univariate, and multivariate, feature selection methods, such as the Boruta algorithm, are applied. Subsequently, an optimisation procedure, which utilises random forest algorithm with three dataset pairs combinations, is performed. The resulting optimal gene sets are then combined and further subjected to network analysis and pathway enrichment analysis so as to obtain information related to their biological relevance. The microarray datasets were analysed via the MCP‐counter, CIBERSORT, TIMER, EPIC, and quanTIseq deconvolution methods and an estimation of cell type abundances for each dataset sample were identified. The differences in the cell type abundances, between the adjacent and tumour sample groups, were then assessed using a Wilcoxon Rank Sum test (p‐value < 0.05). Results The optimal gene signature sets, derived from each of the data pairs combination, achieved AUC values ranging from 0.959 to 0.988 in external validation sets using Random Forest model. CLEC1B and PTTG1 genes are retrieved across each optimal set. Among the signature genes, PTTG1, AURKA, and UBE2C genes are found to be involved in the regulation of mitotic sister chromatid separation and anaphase‐promoting complex (APC) dependent catabolic process (adjusted p‐value < 0.001). Additionally, the application of deconvolution algorithms revealed significant changes in cell type abundances of Regulatory T (Treg) cells, M0 and M1 macrophages, and T CD8+ cells between adjacent and tumour samples. Conclusion We identified ECM1 gene as a potential immune‐related marker acting through immune cell migration and macrophage polarisation. Our results indicate that macrophages, such as M0 macrophage and M1 macrophage cells, undergo significant changes in HCC TME. Moreover, our immune deconvolution approach revealed significant infiltration of Treg cells and M0 macrophages, and a significant decrease in T CD8+ cells and M1 macrophages in tumour samples.https://doi.org/10.1002/cam4.4941gene signaturehepatocellular carcinomaimmune deconvolutiontumor microenvironment |
| spellingShingle | Basak Bahcivanci Roshan Shafiha Georgios V. Gkoutos Animesh Acharjee Associating transcriptomics data with inflammatory markers to understand tumour microenvironment in hepatocellular carcinoma Cancer Medicine gene signature hepatocellular carcinoma immune deconvolution tumor microenvironment |
| title | Associating transcriptomics data with inflammatory markers to understand tumour microenvironment in hepatocellular carcinoma |
| title_full | Associating transcriptomics data with inflammatory markers to understand tumour microenvironment in hepatocellular carcinoma |
| title_fullStr | Associating transcriptomics data with inflammatory markers to understand tumour microenvironment in hepatocellular carcinoma |
| title_full_unstemmed | Associating transcriptomics data with inflammatory markers to understand tumour microenvironment in hepatocellular carcinoma |
| title_short | Associating transcriptomics data with inflammatory markers to understand tumour microenvironment in hepatocellular carcinoma |
| title_sort | associating transcriptomics data with inflammatory markers to understand tumour microenvironment in hepatocellular carcinoma |
| topic | gene signature hepatocellular carcinoma immune deconvolution tumor microenvironment |
| url | https://doi.org/10.1002/cam4.4941 |
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