Yao Sheng, Yu Yuanquan, Xu Liyi, Pan Xiang
Department of Gastroenterology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Front Oncol. 2023 Jan 9;12:1072576. doi: 10.3389/fonc.2022.1072576. eCollection 2022.
Digestive system pan-cancer is one of the lethal malignant tumors, which have the propensity for poor prognosis and difficult treatment. Endoplasmic reticulum (ER) stress has served as a pivotal role in the progression of the tumor, while the implication of ER stress on digestive system pan-cancers still needs elucidation, especially from the perspective of clinical outcome and that of genomic features.
First, Among the ER STRESS factors from the REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR (113 genes) and HALLMARK_UNFOLDED_PROTEIN_RESPONSE (92 genes) terms, 153 ER STRESS regulators were identified after removing replicates. The somatic mutation data and copy number variation data of gastrointestinal pan-cancer were downloaded from The Cancer Genome Atlas (TCGA) database. Then, we explored the clinical outcome and genetic mutation of ER stress-related differentially expressed genes (DEGs) by multiple bioinformatics analysis. Subsequently, we analyzed the Spearman correlation between the drug sensitivity of 179 gastrointestinal anticancer drugs and the transcriptional expression of 153 ER stress factors in 769 cancer cell lines of the GDSC2 cohort. Next, ssGSEA method was used to quantify the immune cell infiltration scores in the tumor microenvironment, and Spearman correlation was used to calculate the correlation between ER stress scores and immune cell infiltration. Finally, we analyzed the cellular origin of ER stress factor dysregulation.
We analyzed the genomic changes and clinical outcomes of ER stress factors in different tumors of gastrointestinal pan-cancer. Endoplasmic reticulum stress factor (ER) in digestive tract tumors showed high SNV mutation frequency, less methylation dysregulation and was associated with multiple oncogenic pathways. Endoplasmic reticulum stress factor (ER) is a risk factor for many cancers, but the effect on overall survival in rectal adenocarcinoma is opposite to that in other gastrointestinal tumors. And ER stress factors are highly correlated with drugs that target important pathways.
Based on the clinical prognosis and genomic analysis of ER stress-related factors in patients with gastrointestinal pan-cancer, this study provides a new direction for further research on gastrointestinal pan-cancer.
消化系统泛癌是致命的恶性肿瘤之一，预后较差且治疗困难。内质网（ER）应激在肿瘤进展中起关键作用，而ER应激对消化系统泛癌的影响仍需阐明，尤其是从临床结局和基因组特征的角度。
首先，在REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR（113个基因）和HALLMARK_UNFOLDED_PROTEIN_RESPONSE（92个基因）术语中的ER应激因子中，去除重复项后鉴定出153个ER应激调节因子。从癌症基因组图谱（TCGA）数据库下载胃肠道泛癌的体细胞突变数据和拷贝数变异数据。然后，我们通过多种生物信息学分析探索了ER应激相关差异表达基因（DEG）的临床结局和基因突变。随后，我们分析了179种胃肠道抗癌药物的药物敏感性与GDSC2队列769个癌细胞系中153个ER应激因子的转录表达之间的Spearman相关性。接下来，使用单样本基因集富集分析（ssGSEA）方法量化肿瘤微环境中的免疫细胞浸润分数，并使用Spearman相关性计算ER应激分数与免疫细胞浸润之间的相关性。最后，我们分析了ER应激因子失调的细胞起源。
我们分析了胃肠道泛癌不同肿瘤中ER应激因子的基因组变化和临床结局。消化道肿瘤中的内质网应激因子（ER）显示出高单核苷酸变异（SNV）突变频率，甲基化失调较少，并且与多种致癌途径相关。内质网应激因子（ER）是许多癌症的危险因素，但对直肠腺癌总生存期的影响与其他胃肠道肿瘤相反。并且ER应激因子与靶向重要途径的药物高度相关。
基于胃肠道泛癌患者ER应激相关因子的临床预后和基因组分析，本研究为胃肠道泛癌的进一步研究提供了新方向。
