PO.BCS01.04 · 生物信息与计算

胃肠上皮化生的单细胞多组学表征揭示 GC 进展高风险病变的潜在遗传、表观遗传和异构体特征

Single-cell multi-omic characterization of gastric intestinal metaplasia reveals potential genetic, epigenetic and isoform signatures of lesions at high risk for GC progression

编号 4130 展板 10 时间 4/21 09:00–12:00 区域 Section 2 主讲 Dongin Lee, PhD

分会场 Application of Bioinformatics to Cancer Biology 4

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作者与单位 Authors & Affiliations

Dongin Lee¹, Xiangqi Bai¹, Sue Grimes¹, Kyungtae Lee¹, Yan Wang¹, Charlotte Wong¹, Anuja Sathe¹, Ignacio Wichmann¹, Youlim Kim², Rithika Meka¹, Renee Long¹, Allison Im¹, Billy Lau¹, Robert Huang¹, Hanlee P. Ji¹

¹Medicine, Stanford University School of Medicine, Stanford, CA,²Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA

摘要 Abstract

中文摘要

在全球范围内，胃癌（GC）是第五大最常见的恶性肿瘤，也是癌症相关死亡的第三大原因。胃肠上皮化生（GIM）是 GC 的前驱病变。然而，只有少数 GIM 病变会进展为 GC。一个关键挑战是识别 GIM 中能够预测其发展为浸润性癌症风险的基因组、分子和细胞特征。一旦识别出这些特征，就可以对高风险发展为 GC 的患者进行“拦截”。我们对 GIM 病变的内镜活检样本进行了单细胞多组学分析。这些患者采用双活检方法进行了 GC 风险评估。我们利用病理结果，基于胃肠上皮化生评估操作链接（OLGIM）确定临床风险分期。临床分期包括属于低风险的 I 期和 II 期，以及属于高风险的 III 期和 IV 期。每份活检样本均接受单细胞 RNA-seq 和染色质转座酶可及性单细胞检测（ATAC）。因此，我们对每个细胞都拥有这两种基因组读出数据。此外，我们使用单细胞长读长测序来识别转录本异构体和突变。总体而言，我们获得了以下 GIM 的单细胞特征，包括：（1）基因表达，（2）染色质可及性，（3）拷贝数畸变，（4）体细胞变异，以及（5）异构体表达。我们比较了高风险组和低风险组之间的单细胞基因组特征。例如，我们观察到在肠样干细胞中特异性表达、与潜在胃癌起始细胞相关的关键基因——如 CDH17、SI 和 CPS1——在高风险组中表达更高，该组在相同基因上也表现出染色质可及性增加。此外，我们在两组之间检测到胃相关基因的差异异构体使用，这意味着异构体变化与 GC 进展相关。这些发现提供了与发展为 GC 的高风险相关的 GIM 的基因组、分子和细胞特征。

查看英文原文 English abstract

Worldwide, gastric cancer (GC) is the fifth most common malignancy and the third leading cause of cancer-related deaths. Gastric intestinal metaplasia (GIM) is a precursor lesion of GC. However, only a small number of GIM lesions progress to GC. A key challenge is identifying the genomic, molecular and cellular features of GIM that predict their risk of becoming invasive cancer. Once these features are identified, one could “intercept” patients at high risk for developing GC. We conducted a single-cell multi-omic analysis of endoscopic biopsies of GIM lesions. These patients underwent GC risk evaluation using a two-biopsy approach. We used the pathology results to determine a clinical risk stage based on the Operative Link on Gastric Intestinal Metaplasia Assessment (OLGIM). Clinical stages include I and II which are low risk versus III and IV which are high risk. Each biopsy underwent single cell RNA-seq and single cell assay for transposase accessibility of chromatin (ATAC). Therefore, we had both of these genomic readouts for each cell. In addition, we used single cell long read sequencing to identify transcript isoforms and mutations. Overall, we obtained the following single cell cell features of GIM which included: (1) gene expression, (2) chromatin accessibility, (3) copy number aberrations, (4) somatic variants, and (5) isoform expression. We compared the single cell genomics features between high-risk and low-risk groups. For example, we observed that key genes specifically expressed in intestinal-like stem cells, which are linked to potential gastric cancer-initiating cells-such as CDH17 , SI and CPS1 -were more highly expressed among the high-risk group, which also exhibited increased chromatin accessibility at the same genes. Furthermore, we detected differential isoform usage of gastric-related genes between the two groups, which implies that isoform changes are related to GC progression. These findings provide genomic, molecular and cellular features of GIMs that are associated with high risk of developing GC.

利益披露 Disclosure

D. Lee, None.. X. Bai, None.. S. Grimes, None.. K. Lee, None.. Y. Wang, None.. C. Wong, None.. A. Sathe, None.. I. Wichmann, None.. Y. Kim, None.. R. Meka, None.. R. Long, None.. A. Im, None.. B. Lau, None.. R. Huang, None.. H. P. Ji, None.

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