Characterization of genomic alterations and neoantigens and analysis of immune infiltration identified therapeutic and prognostic biomarkers in adenocarcinoma at the gastroesophageal junction
ObjectivesAdenocarcinoma at the gastroesophageal junction (ACGEJ) refers to a malignant tumor that occurs at the esophagogastric junction. Despite some progress in targeted therapies for HER2, FGFR2, EGFR, MET, Claudin 18.2 and immune checkpoints in ACGEJ tumors, the 5-year survival rate of patients...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.941868/full |
| _version_ | 1798019196737552384 |
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| author | Yueqiong Lao Yuqian Wang Jie Yang Tianyuan Liu Yuling Ma Yingying Luo Yanxia Sun Kai Li Xuan Zhao Xiangjie Niu Yiyi Xi Ce Zhong |
| author_facet | Yueqiong Lao Yuqian Wang Jie Yang Tianyuan Liu Yuling Ma Yingying Luo Yanxia Sun Kai Li Xuan Zhao Xiangjie Niu Yiyi Xi Ce Zhong |
| author_sort | Yueqiong Lao |
| collection | DOAJ |
| description | ObjectivesAdenocarcinoma at the gastroesophageal junction (ACGEJ) refers to a malignant tumor that occurs at the esophagogastric junction. Despite some progress in targeted therapies for HER2, FGFR2, EGFR, MET, Claudin 18.2 and immune checkpoints in ACGEJ tumors, the 5-year survival rate of patients remains poor. Thus, it is urgent to explore genomic alterations and neoantigen characteristics of tumors and identify CD8+ T-cell infiltration-associated genes to find potential therapeutic targets and develop a risk model to predict ACGEJ patients’ overall survival (OS).MethodsWhole-exome sequencing (WES) was performed on 55 paired samples from Chinese ACGEJ patients. Somatic mutations and copy number variations were detected by Strelka2 and FACETS, respectively. SigProfiler and SciClone were employed to decipher the mutation signature and clonal structure of each sample, respectively. Neoantigens were predicted using the MuPeXI pipeline. RNA sequencing (RNA-seq) data of ACGEJ samples from our previous studies and The Cancer Genome Atlas (TCGA) were used to identify genes significantly associated with CD8+ T-cell infiltration by weighted gene coexpression network analysis (WGCNA). To construct a risk model, we conducted LASSO and univariate and multivariate Cox regression analyses.ResultsRecurrent MAP2K7, RNF43 and RHOA mutations were found in ACGEJ tumors. The COSMIC signature SBS17 was associated with ACGEJ progression. CCNE1 and VEGFA were identified as putative CNV driver genes. PI3KCA and TP53 mutations conferred selective advantages to cancer cells. The Chinese ACGEJ patient neoantigen landscape was revealed for the first time, and 58 potential neoantigens common to TSNAdb and IEDB were identified. Compared with Siewert type II samples, Siewert type III samples had significant enrichment of the SBS17 signature, a lower TNFRSF14 copy number, a higher proportion of samples with complex clonal architecture and a higher neoantigen load. We identified 10 important CD8+ T-cell infiltration-related Hub genes (CCL5, CD2, CST7, GVINP1, GZMK, IL2RB, IKZF3, PLA2G2D, P2RY10 and ZAP70) as potential therapeutic targets from the RNA-seq data. Seven CD8+ T-cell infiltration-related genes (ADAM28, ASPH, CAMK2N1, F2R, STAP1, TP53INP2, ZC3H3) were selected to construct a prognostic model. Patients classified as high risk based on this model had significantly worse OS than low-risk patients, which was replicated in the TCGA-ACGEJ cohort.ConclusionsThis study provides new neoantigen-based immunotherapeutic targets for ACGEJ treatment and effective disease prognosis biomarkers. |
| first_indexed | 2024-04-11T16:36:38Z |
| format | Article |
| id | doaj.art-229f217790d74a9fbe00f78bc1ef3633 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-11T16:36:38Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-229f217790d74a9fbe00f78bc1ef36332022-12-22T04:13:47ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-11-011210.3389/fonc.2022.941868941868Characterization of genomic alterations and neoantigens and analysis of immune infiltration identified therapeutic and prognostic biomarkers in adenocarcinoma at the gastroesophageal junctionYueqiong LaoYuqian WangJie YangTianyuan LiuYuling MaYingying LuoYanxia SunKai LiXuan ZhaoXiangjie NiuYiyi XiCe ZhongObjectivesAdenocarcinoma at the gastroesophageal junction (ACGEJ) refers to a malignant tumor that occurs at the esophagogastric junction. Despite some progress in targeted therapies for HER2, FGFR2, EGFR, MET, Claudin 18.2 and immune checkpoints in ACGEJ tumors, the 5-year survival rate of patients remains poor. Thus, it is urgent to explore genomic alterations and neoantigen characteristics of tumors and identify CD8+ T-cell infiltration-associated genes to find potential therapeutic targets and develop a risk model to predict ACGEJ patients’ overall survival (OS).MethodsWhole-exome sequencing (WES) was performed on 55 paired samples from Chinese ACGEJ patients. Somatic mutations and copy number variations were detected by Strelka2 and FACETS, respectively. SigProfiler and SciClone were employed to decipher the mutation signature and clonal structure of each sample, respectively. Neoantigens were predicted using the MuPeXI pipeline. RNA sequencing (RNA-seq) data of ACGEJ samples from our previous studies and The Cancer Genome Atlas (TCGA) were used to identify genes significantly associated with CD8+ T-cell infiltration by weighted gene coexpression network analysis (WGCNA). To construct a risk model, we conducted LASSO and univariate and multivariate Cox regression analyses.ResultsRecurrent MAP2K7, RNF43 and RHOA mutations were found in ACGEJ tumors. The COSMIC signature SBS17 was associated with ACGEJ progression. CCNE1 and VEGFA were identified as putative CNV driver genes. PI3KCA and TP53 mutations conferred selective advantages to cancer cells. The Chinese ACGEJ patient neoantigen landscape was revealed for the first time, and 58 potential neoantigens common to TSNAdb and IEDB were identified. Compared with Siewert type II samples, Siewert type III samples had significant enrichment of the SBS17 signature, a lower TNFRSF14 copy number, a higher proportion of samples with complex clonal architecture and a higher neoantigen load. We identified 10 important CD8+ T-cell infiltration-related Hub genes (CCL5, CD2, CST7, GVINP1, GZMK, IL2RB, IKZF3, PLA2G2D, P2RY10 and ZAP70) as potential therapeutic targets from the RNA-seq data. Seven CD8+ T-cell infiltration-related genes (ADAM28, ASPH, CAMK2N1, F2R, STAP1, TP53INP2, ZC3H3) were selected to construct a prognostic model. Patients classified as high risk based on this model had significantly worse OS than low-risk patients, which was replicated in the TCGA-ACGEJ cohort.ConclusionsThis study provides new neoantigen-based immunotherapeutic targets for ACGEJ treatment and effective disease prognosis biomarkers.https://www.frontiersin.org/articles/10.3389/fonc.2022.941868/fulladenocarcinoma at the gastroesophageal junctiongenome and transcriptometumor neoantigensCD8+ T cellstherapeutic biomarkersprognostic prediction |
| spellingShingle | Yueqiong Lao Yuqian Wang Jie Yang Tianyuan Liu Yuling Ma Yingying Luo Yanxia Sun Kai Li Xuan Zhao Xiangjie Niu Yiyi Xi Ce Zhong Characterization of genomic alterations and neoantigens and analysis of immune infiltration identified therapeutic and prognostic biomarkers in adenocarcinoma at the gastroesophageal junction Frontiers in Oncology adenocarcinoma at the gastroesophageal junction genome and transcriptome tumor neoantigens CD8+ T cells therapeutic biomarkers prognostic prediction |
| title | Characterization of genomic alterations and neoantigens and analysis of immune infiltration identified therapeutic and prognostic biomarkers in adenocarcinoma at the gastroesophageal junction |
| title_full | Characterization of genomic alterations and neoantigens and analysis of immune infiltration identified therapeutic and prognostic biomarkers in adenocarcinoma at the gastroesophageal junction |
| title_fullStr | Characterization of genomic alterations and neoantigens and analysis of immune infiltration identified therapeutic and prognostic biomarkers in adenocarcinoma at the gastroesophageal junction |
| title_full_unstemmed | Characterization of genomic alterations and neoantigens and analysis of immune infiltration identified therapeutic and prognostic biomarkers in adenocarcinoma at the gastroesophageal junction |
| title_short | Characterization of genomic alterations and neoantigens and analysis of immune infiltration identified therapeutic and prognostic biomarkers in adenocarcinoma at the gastroesophageal junction |
| title_sort | characterization of genomic alterations and neoantigens and analysis of immune infiltration identified therapeutic and prognostic biomarkers in adenocarcinoma at the gastroesophageal junction |
| topic | adenocarcinoma at the gastroesophageal junction genome and transcriptome tumor neoantigens CD8+ T cells therapeutic biomarkers prognostic prediction |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.941868/full |
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