Human gastric cancer is a highly lethal disease, but the underlying multiomic molecular signatures remain largely unclear. Here, we performed multi-regional sampling, parallel single-cell multiomics sequencing and integrated analyses of human gastric cancer. We identified common transcriptomic alterations of gastric cancer cells, such as aberrant down-regulation of genes associated with normal stomach function and up-regulation of KRT7, PI3, S100A4, etc. Surprisingly, aberrant and prevalent up-regulation of genes highly expressed in normal colorectal epithelial cells were also identified in cancer cells, which may be partially regulated by promoter chromatin accessibility and DNA methylation levels. We revealed the single-cell DNA methylome landscape of gastric cancer, and identified candidate DNA methylation biomarkers, such as hypermethylated promoters of TMEM240 and HAGLROS, and hypomethylated promoters of TRPM2-AS and HRH1. Additionally, the relationships between genetic lineages, DNA methylation and transcriptomic clusters were systematically revealed at single-cell level. We showed that DNA methylation heterogeneities were mainly among different genetic lineages of cancer cells. Moreover, we found that DNA methylation levels of cancer cells with poorer differentiation states tend to be higher than those of cancer cells with better differentiation states in the primary tumor within the same patient, although still lower than in normal gastric epithelial cells. Cancer cells with poorer differentiation states also prevalently down-regulated MUC1 expression and immune-related pathways, and had poor infiltration of CD8+ T cells. Our study dissected the molecular signatures of intratumoral heterogeneities and differentiation states of human gastric cancer using integrative single-cell multiomics analyses.
人类胃癌是一种高致死性疾病，但其潜在的多组学分子特征在很大程度上仍不明确。本研究通过多区域采样、并行单细胞多组学测序及整合分析人类胃癌样本，揭示了胃癌细胞的共性转录组改变，例如与正常胃功能相关基因的异常下调以及KRT7、PI3、S100A4等基因的上调。值得注意的是，研究还发现癌细胞中异常且普遍上调了在正常结直肠上皮细胞中高表达的基因，这可能部分受启动子染色质可及性和DNA甲基化水平调控。我们描绘了胃癌的单细胞DNA甲基组景观，并筛选出潜在的DNA甲基化生物标志物，如TMEM240和HAGLROS的高甲基化启动子，以及TRPM2-AS和HRH1的低甲基化启动子。此外，研究在单细胞水平系统揭示了遗传谱系、DNA甲基化与转录组聚类之间的关系。我们发现DNA甲基化异质性主要存在于癌细胞的不同遗传谱系之间。值得注意的是，在同一患者的原发肿瘤内，分化状态较差的癌细胞DNA甲基化水平往往高于分化状态较好的癌细胞，但仍低于正常胃上皮细胞。分化状态较差的癌细胞还普遍下调MUC1表达和免疫相关通路，并呈现CD8+ T细胞浸润不足的特征。本研究通过整合单细胞多组学分析，深入解析了人类胃癌的瘤内异质性分子特征及分化状态。
肿瘤(癌症)患者之家