Field Cancerization in the Intestinal Epithelium of Patients With Crohn's Ileocolitis
Field Cancerization in the Intestinal Epithelium of Patients With Crohn's Ileocolitis
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DOI：
10.1053/j.gastro.2011.12.004
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发表时间：
2012-04-01
期刊：
影响因子：
29.4
通讯作者：
Graham, Trevor A.
中科院分区：
文献类型：
--
作者：
Galandiuk, Susan;Rodriguez-Justo, Manuel;Graham, Trevor A.
背景与目的：克罗恩病患者的肿瘤往往是多灶性的，因此现场癌变（用非发育异常但致瘤性克隆替代正常细胞）可能有助于肠道癌变。我们研究了肿瘤前肠细胞克隆的肿瘤发展模式。方法：我们对10例克罗恩病和肠道肿瘤患者的多个肠道区域进行了遗传分析。2例患者有多灶性瘤形成;从3例患者中收集纵切片。对单个隐窝进行显微解剖和基因分型;使用克隆依赖性分析来确定导致肿瘤发展的突变的顺序和时间。研究结果：在肿瘤中观察到的KRAS、CDKN 2A（p16）和TP 53中的相同突变也存在于非肿瘤、非发育不良和发育不良上皮中。在2例患者中，在肿瘤发生前4年在非肿瘤上皮中检测到致癌突变。在1例患者的结肠全长沿着多个位点检测到相同的突变（TP 53 p.R248 W）;这是同步肿瘤和多个发育异常区域的明显创始者突变。TP 53、CDKN 2A和KRAS的破坏都被视为肿瘤发生中可能的初始事件;不同病变的突变序列（肿瘤发展途径）不同。结论：克罗恩病患者的肠上皮细胞中可广泛生长瘤前克隆。因此，克罗恩病患者肿瘤的节段性切除可能会留下残留的癌前病变，而异型增生可能是癌症风险的不可靠生物标志物。肿瘤前克隆的行为特征可用于预测肠肿瘤的发展。
BACKGROUND & AIMS: Tumors that develop in patients with Crohn's disease tend be multifocal, so field cancerization (the replacement of normal cells with non-dysplastic but tumorigenic clones) might contribute to intestinal carcinogenesis. We investigated patterns of tumor development from pretumor intestinal cell clones. METHODS: We performed genetic analyses of multiple areas of intestine from 10 patients with Crohn's disease and intestinal neoplasia. Two patients had multifocal neoplasia; longitudinal sections were collected from 3 patients. Individual crypts were microdissected and genotyped; clonal dependency analysis was used to determine the order and timing of mutations that led to tumor development. RESULTS: The same mutations in KRAS, CDKN2A(p16), and TP53 that were observed in neoplasias were also present in nontumor, nondysplastic, and dysplastic epithelium. In 2 patients, carcinogenic mutations were detected in nontumor epithelium 4 years before tumors developed. The same mutation (TP53 p.R248W) was detected at multiple sites along the entire length of the colon from 1 patient; it was the apparent founder mutation for synchronous tumors and multiple dysplastic areas. Disruption of TP53, CDKN2A, and KRAS were all seen as possible initial events in tumorigenesis; the sequence of mutations (the tumor development pathway) differed among lesions. CONCLUSIONS: Pretumor clones can grow extensively in the intestinal epithelium of patients with Crohn's disease. Segmental resections for neoplasia in patients with Crohn's disease might therefore leave residual pretumor disease, and dysplasia might be an unreliable biomarker for cancer risk. Characterization of the behavior of pretumor clones might be used to predict the development of intestinal neoplasia.