Hong Yi, Ho Kok Sun, Eu Kong Weng, Cheah Peh Yean
Department of Colorectal Surgery, Singapore General Hospital, Singapore, Republic of Singapore.
Clin Cancer Res. 2007 Feb 15;13(4):1107-14. doi: 10.1158/1078-0432.CCR-06-1633.
The causative genes for autosomal dominantly inherited familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer have been well characterized. There is, however, another 10% to 15% of early onset colorectal cancers (CRC) in which the genetic components are unclear. In this study, we used microarray technology to systematically search for differentially expressed genes in early onset CRC.
Young patients with non-FAP or non-hereditary nonpolyposis colorectal cancer, and healthy controls were age- (<or=50 years old), ethnicity- (Chinese), and tissue-matched. RNAs extracted from colonic mucosa specimens were analyzed using GeneChip U133-Plus 2.0 Array.
Seven genes, CYR61, UCHL1, FOS, FOS B, EGR1, VIP, and KRT24, were consistently up-regulated in the mucosa of all six patients compared with the mucosa from four healthy controls. The overexpression of these genes was independently validated with a testing set of six patients and six healthy controls. Principal component analysis clustered the healthy control specimens separately from the patient specimens. Real-time PCR quantification with SYBR-Green on nine other patient specimens not previously used in microarray assays confirmed the up-regulation of these seven genes. These genes function in a multitude of biological processes ranging from transcription, angiogenesis, adhesion, and inflammatory regulation to protein catabolism in various cellular compartments, from extracellular to the nucleus. They integrate known tumorigenesis (Wnt, PI3K, MAP kinase, hypoxia, G protein-coupled receptor), neurologic, insulin-signaling, and NFAT-immune pathways into an intricate biological network.
The data suggest that the patient's mucosa is primed for tumorigenesis when cellular homeostasis is disrupted, and that the seven overexpressed genes could potentially predict early onset CRC.
常染色体显性遗传的家族性腺瘤性息肉病（FAP）和遗传性非息肉病性结直肠癌的致病基因已得到充分表征。然而，另有10%至15%的早发性结直肠癌（CRC），其遗传成分尚不清楚。在本研究中，我们使用微阵列技术系统地搜索早发性CRC中差异表达的基因。
非FAP或非遗传性非息肉病性结直肠癌的年轻患者以及健康对照在年龄（≤50岁）、种族（中国人）和组织方面相匹配。使用基因芯片U133 Plus 2.0阵列分析从结肠黏膜标本中提取的RNA。
与四名健康对照的黏膜相比，六名患者的所有黏膜中CYR61、UCHL1、FOS、FOS B、EGR1、VIP和KRT24这七个基因均持续上调。这七个基因的过表达在另外一组六名患者和六名健康对照中得到独立验证。主成分分析将健康对照标本与患者标本分开聚类。对另外九个未用于微阵列分析的患者标本进行SYBR Green实时PCR定量，证实了这七个基因的上调。这些基因在多种生物学过程中发挥作用，从转录、血管生成、黏附、炎症调节到不同细胞区室（从细胞外到细胞核）的蛋白质分解代谢。它们将已知的肿瘤发生（Wnt、PI3K、MAP激酶、缺氧、G蛋白偶联受体）、神经、胰岛素信号和NFAT免疫途径整合到一个复杂的生物网络中。
数据表明，当细胞内稳态被破坏时，患者的黏膜就为肿瘤发生做好了准备，并且这七个过表达的基因可能潜在地预测早发性CRC。
