背景:食管鳞状细胞癌(ESCC)预后不良,是最致命的胃肠道恶性肿瘤之一。尽管进行了大量的转录组学研究以了解其分子基础,人群特异性差异对该疾病的影响仍有待研究.
目的:本研究旨在调查从六个不同的全球人群中获得的ESCC样本中基因表达模式的人群特异性差异。鉴定差异表达基因(DEG)及其相关途径,并确定ESCC诊断和预后的潜在生物标志物。此外,这项研究破译了ESCC中特定人群的微生物和化学危险因素。
方法:我们通过分析微阵列数据集,比较了来自六个不同全球人群的ESCC样品的基因表达模式。要识别DEG,我们进行了严格的质量控制和线性建模。我们交叉比较了每个群体的DEG列表以及ESCCATLAS,以鉴定已知和新的DEG。我们使用癌症基因组图谱计划(TCGA)数据进行了生存分析,以确定新型DEG中ESCC诊断和预后的潜在生物标志物。最后,我们进行了比较功能富集和毒理基因组分析.
结果:在这里,我们报告了19个在群体中具有不同表达模式的基因,表明ESCC中的人群特异性差异。此外,我们发现了166个新颖的DEG,如ENDOU,SLCO1B3、KCNS3、IFI35等。存活分析确定了对ESCC存活至关重要的三个新基因(CHRM3、CREG2、H2AC6)。值得注意的是,我们的发现表明,ECM相关的基因本体论术语和通路在ESCC的DEGs中显著丰富。我们还发现了免疫反应和微生物感染相关途径中的群体特异性变异,其中包括富含HPV的基因。减数分裂,利什曼病,和人类巨细胞病毒。我们的毒物基因组分析确定吸烟是主要的危险因素,顺铂是与人群中最大数量的DEG相互作用的主要药物化学物质。
结论:这项研究为ESCC中基因表达模式及其相关途径的群体特异性差异提供了新的见解。我们的研究结果表明,细胞外基质(ECM)组织的变化可能对这种癌症的发展和进展至关重要。环境和遗传因素在疾病中起着重要作用。鉴定出的新型DEG可以作为诊断的潜在生物标志物,预后和治疗。
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) has a poor prognosis and is one of the deadliest gastrointestinal malignancies. Despite numerous transcriptomics studies to understand its molecular basis, the impact of population-specific differences on this disease remains unexplored.
OBJECTIVE: This study aimed to investigate the population-specific differences in gene expression patterns among ESCC samples obtained from six distinct global populations, identify differentially expressed genes (DEGs) and their associated pathways, and identify potential biomarkers for ESCC diagnosis and prognosis. In addition, this study deciphers population specific microbial and chemical risk factors in ESCC.
METHODS: We compared the gene expression patterns of ESCC samples from six different global populations by analyzing microarray datasets. To identify DEGs, we conducted stringent quality control and employed linear modeling. We cross-compared the resulting DEG lists of each populations along with ESCC ATLAS to identify known and novel DEGs. We performed a survival analysis using The Cancer Genome Atlas Program (TCGA) data to identify potential biomarkers for ESCC diagnosis and prognosis among the novel DEGs. Finally, we performed comparative functional enrichment and toxicogenomic analysis.
RESULTS: Here we report 19 genes with distinct expression patterns among populations, indicating population-specific variations in ESCC. Additionally, we discovered 166 novel DEGs, such as ENDOU, SLCO1B3, KCNS3, IFI35, among others. The survival analysis identified three novel genes (CHRM3, CREG2, H2AC6) critical for ESCC survival. Notably, our findings showed that ECM-related gene ontology terms and pathways were significantly enriched among the DEGs in ESCC. We also found population-specific variations in immune response and microbial infection-related pathways which included genes enriched for HPV, Ameobiosis, Leishmaniosis, and Human Cytomegaloviruses. Our toxicogenomic analysis identified tobacco smoking as the primary risk factor and cisplatin as the main drug chemical interacting with the maximum number of DEGs across populations.
CONCLUSIONS: This study provides new insights into population-specific differences in gene expression patterns and their associated pathways in ESCC. Our findings suggest that changes in extracellular matrix (ECM) organization may be crucial to the development and progression of this cancer, and that environmental and genetic factors play important roles in the disease. The novel DEGs identified may serve as potential biomarkers for diagnosis, prognosis and treatment.