Gene expression profiling of colorectal normal mucosa, adenoma and adenocarcinoma tissues. Homo sapiens

Approximately two decades ago, Vogelstein and Fearon proposed the adenoma-carcinoma sequence of sporadic CRC development and illustrated the accumulation of genetic alterations during the stepwise progression, thereby providing a guideline for clinical practice. Although the detection and excision of precancerous lesions could prevent colorectal cancer and reduce mortality, 6% of adenomas will ultimately develop into colorectal cancer. Thus, this genetic model for colorectal tumorigenesis may not completely reflect the complex essence of the disease and whether the mode of initiation of the events in the multistep progression affects the outcome of CRC is still unknown. In this study, mRNA and miRNA expression profiling was performed with human colorectal tissues, including normal mucosa, adenoma and adenocarcinoma. Then, an integrated approach was adopted to establish the regulatory interaction networks that were correlated with colorectal carcinogenesis. Finally, a 55-gene signature whose expression was down-regulated in precancerous lesions compared to normal tissue was identified as a potential early indicator of CRC survival. The results suggested that genes related to immunity and homeostasis played a critical role in protection against adenoma initiation and that the altered molecular events that influence colorectal cancer prognosis may be set in an early, precancerous stage. Overall design: Four types of human colorectal tissues were selected by colonoscopic resection or colorectal surgery, including 12 normal mucosae, 21 low-grade adenomas (mild or moderate atypical hyperplasia), 30 high-grade adenomas (severe atypical hyperplasia or carcinoma in situ) and 25 adenocarcinomas. Gene expression profiling analysis of these samples was performed using Agilent 4x44K human whole genome gene expression microarray (G4112F).

约二十年前，Vogelstein与Fearon提出了散发性结直肠癌（colorectal cancer, CRC）发生的腺瘤-腺癌序列学说，阐明了疾病逐步进展过程中遗传变异的积累过程，为临床实践提供了重要指导。尽管检出并切除癌前病变可预防结直肠癌、降低患者病死率，但仍有6%的腺瘤最终会进展为结直肠癌。由此可见，这套结直肠癌发生的遗传模型尚无法完全阐释该疾病的复杂病理本质，而多步骤癌变进程中事件的启动模式是否会影响结直肠癌预后，目前仍不明确。本研究针对人类结直肠组织（涵盖正常黏膜、腺瘤与腺癌组织）开展了信使RNA（messenger RNA, mRNA）与微小RNA（microRNA, miRNA）表达谱分析。随后通过整合分析策略构建了与结直肠癌发生密切相关的调控互作网络。最终，本研究鉴定出一组55基因特征集：相较于正常组织，该特征集在癌前病变中呈表达下调趋势，可作为结直肠癌预后评估的潜在早期标志物。研究结果显示，与免疫应答及内环境稳态相关的基因在抑制腺瘤启动过程中发挥关键作用；而影响结直肠癌预后的分子事件改变，可能早在癌前病变阶段就已启动。研究整体设计：通过结肠镜下切除术或结直肠手术获取四类人类结直肠组织样本，具体包括12例正常黏膜组织、21例低级别腺瘤（伴轻度或中度非典型增生）、30例高级别腺瘤（伴重度非典型增生或原位癌（carcinoma in situ））以及25例腺癌组织。本研究采用安捷伦（Agilent）4x44K人类全基因组基因表达芯片（G4112F）对上述样本完成基因表达谱分析。