Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Department of Joint Research Laboratory of Clinical Medicine, Fujita Health University School of Medicine, Aichi, Japan.
Cancer Med. 2022 Dec;11(24):5066-5078. doi: 10.1002/cam4.4810. Epub 2022 May 10.
The objective of this study was to elucidate the molecular background of sessile serrated adenoma/polyp (SSA/P) endoscopically resected with comprehensive gene expression analysis. Gene expression profiling was performed for 10 tumor-normal pairs of SSA/P. Cluster analysis, gene set enrichment analysis (GSEA), and consensus molecular subtype (CMS) classification of colorectal cancer (CRC) were applied to our transcriptome analysis. Unsupervised cluster analysis showed that the gene expression profile of SSA/Ps is different from that of adjacent normal epithelial cells, even in the very early stage of tumorigenesis. According to the CMS classification, our microarray data indicated that SSA/Ps were classified as CMS1. GSEA demonstrated a strong association between SSA/P and microsatellite instability-high (MSI-H) CRC (p < 10 ). Transcriptome analysis of five MSI-related genes (MSH2, MSH6, MLH1, PMS1, and PMS2) and five CRC-related genes (BRAF, KRAS, APC, TP53, and CDX2) showed that CDX2 expression was most severely decreased in SSA/P. Immunohistochemical staining confirmed that CDX2 protein was reduced compared with the surrounding mucosa. Direct sequencing of the BRAF gene showed that the BRAF V600E mutation was detected in only nine of 36 cases. In a mouse model, BRAF, APC, or CDX2 deficiency indicated that the gene expression pattern with loss of CDX2 is more similar to our SSA/Ps compared with those induced by BRAF or APC mutation. Transcriptome analysis of SSA/Ps showed characteristic gene expression with a strong resemblance to MSI-H CRC. Downregulation of CDX2 expression is an essential molecular mechanism involved in the initial stage of SSA/P tumorigenesis. (UMIN000027365).
本研究旨在通过全面的基因表达分析阐明内镜切除的无蒂锯齿状腺瘤/息肉（SSA/P）的分子背景。对 10 对 SSA/P 的肿瘤-正常组织进行基因表达谱分析。应用聚类分析、基因集富集分析（GSEA）和结直肠癌（CRC）共识分子亚型（CMS）分类对我们的转录组分析进行分析。无监督聚类分析显示，SSA/Ps 的基因表达谱与相邻正常上皮细胞不同，即使在肿瘤发生的早期阶段也是如此。根据 CMS 分类，我们的微阵列数据表明 SSA/Ps 被分类为 CMS1。GSEA 表明 SSA/P 与微卫星不稳定高（MSI-H）CRC 之间存在很强的关联（p<10）。五个 MSI 相关基因（MSH2、MSH6、MLH1、PMS1 和 PMS2）和五个 CRC 相关基因（BRAF、KRAS、APC、TP53 和 CDX2）的转录组分析表明，SSA/P 中 CDX2 的表达降低最为严重。免疫组织化学染色证实，与周围粘膜相比，CDX2 蛋白减少。BRAF 基因的直接测序显示，只有 36 例中的 9 例检测到 BRAF V600E 突变。在小鼠模型中，BRAF、APC 或 CDX2 缺失表明，与 BRAF 或 APC 突变诱导的基因表达模式相比，CDX2 缺失的基因表达模式更类似于我们的 SSA/P。SSA/Ps 的转录组分析显示出与 MSI-H CRC 非常相似的特征性基因表达。CDX2 表达下调是 SSA/P 肿瘤发生早期的一个重要分子机制。（UMIN000027365）。
