Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Okayama, Okayama, Japan.
J Gastroenterol. 2019 Feb;54(2):131-140. doi: 10.1007/s00535-018-1489-4. Epub 2018 Jun 28.
The mechanism behind the pathogenesis and carcinogenesis of these neoplasms is not fully understood. The objective of this study was to identify genetic markers and pathways specific to precancerous duodenal adenomas and early stage adenocarcinomas through gene expression analysis.
Gene expression profiling was performed in 4 pairs of duodenal adenoma/adenocarcinomas and corresponding matched normal tissue. Genes with consistent expression differences were identified and confirmed in 7 independent pairs. Gene set enrichment analysis (GSEA) was performed to characterize gene expression profiles of duodenal adenoma/adenocarcinomas, together with immunohistochemical staining of candidate oncogenic genes.
626 probes consistently demonstrated over a twofold expression difference between tumor-normal pairs. Reverse transcriptase polymerase chain reaction of genes with the most prominent difference in expression between tumors and normal mucosa (KLK7, KLK6, CEMIP, MMP7, KRT17, LGR5, G6PC, S100G, APOA1) validated the results of gene expression analysis. GSEA demonstrated a strong association between duodenal adenoma/adenocarcinomas with colorectal adenomas (p < 10) and gene expression patterns seen after APC gene knockout (p < 10), suggesting that the Wnt/β-catenin pathway plays a crucial role in the carcinogenesis of these neoplasms. Immunohistochemical staining of an independent group of duodenal adenomas confirmed over-accumulation of β-catenin in 80.0% (16/20).
Precancerous duodenal adenomas and early stage adenocarcinomas demonstrate gene expression characteristics with a strong resemblance to colorectal adenomas. The results of this study strongly suggest that upregulation of the Wnt/β-catenin pathway is the major factor involved in the initial stages of the carcinogenesis of duodenal adenocarcinomas.
这些肿瘤的发病机制和癌变机制尚未完全了解。本研究的目的是通过基因表达分析鉴定出与癌前十二指肠腺瘤和早期腺癌相关的特定遗传标记物和途径。
对 4 对十二指肠腺瘤/腺癌及其相应的配对正常组织进行基因表达谱分析。在 7 对独立的样本中验证和确认具有一致表达差异的基因。对十二指肠腺瘤/腺癌的基因表达谱进行基因集富集分析（GSEA），并对候选致癌基因进行免疫组织化学染色。
626 个探针在肿瘤-正常对之间表现出一致的两倍以上表达差异。对在肿瘤与正常黏膜之间表达差异最显著的基因（KLK7、KLK6、CEMIP、MMP7、KRT17、LGR5、G6PC、S100G、APOA1）进行逆转录酶聚合酶链反应验证了基因表达分析的结果。GSEA 显示十二指肠腺瘤/腺癌与结直肠腺瘤之间存在强烈关联（p<10），并且与 APC 基因敲除后观察到的基因表达模式相关（p<10），这表明 Wnt/β-catenin 通路在这些肿瘤的癌变过程中起着至关重要的作用。对另一组十二指肠腺瘤的免疫组织化学染色证实，80.0%（16/20）的肿瘤存在β-catenin 过度积累。
癌前十二指肠腺瘤和早期腺癌表现出与结直肠腺瘤非常相似的基因表达特征。本研究结果强烈表明，Wnt/β-catenin 通路的上调是十二指肠腺癌发生癌变的主要因素。
