Institute of Basic Medicine, Key Laboratory of Yunnan Province, The First People's Hospital of Yunnan Province, Kunming, Yunnan 650032, PR China.
Int J Mol Med. 2010 Nov;26(5):631-41. doi: 10.3892/ijmm_00000508.
The colorectal adenoma-carcinoma sequence describes the stepwise progression from normal to dysplastic epithelium and then to carcinoma. Only a small proportion of colorectal adenomas (CRAs) progress to colorectal carcinomas (CRCs). Endoscopic intervention is currently being used on patients with high grade dysplasia CRAs, with diameters of >1 cm, or villous components of >25% who are at higher risk than other CRA sufferers. During the process, biopsy samples are taken for conventional histological diagnosis, but poor pathomorphological sensitivity and specificity greatly limit the diagnostic accuracy. Unfortunately, there are no reliable molecular criteria available that can predict the potential development of CRA to CRC. Gene expression profiles of normal colorectal mucosa (NOR), CRA and different Dukes' stages of CRC biopsy specimens, which represent the gradual progress of the CRA to CRC sequence, were determined by Affymetrix technology. Representative regulated genes were further analyzed by quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC). Intersectional analyses of discriminative expression signatures of CRC vs. CRA and CRA vs. NOR allowed the identification of an intermediate signature of 463 probe sets (psets) that mark the NOR--> CRA-->CRC progression. This signature represents a reservoir of candidate markers for the early diagnosis of higher-risk CRA, thus allowing for timely therapeutic intervention and more selective treatment. A further 279 CRC-specific psets pointing to the malignant transition from CRA to CRC were identified and these could represent potential therapeutic targets for CRC. The reliability of the results was further confirmed by qRT-PCR and IHC analyses of the 4-gene sets randomly selected from the 463 psets.
结直肠腺瘤-癌序列描述了从正常到异型增生上皮，然后到癌的逐步进展。只有一小部分结直肠腺瘤（CRAs）会进展为结直肠癌（CRCs）。目前，对于高级别异型增生 CRA、直径>1cm 或绒毛成分>25%的患者，内镜干预正在用于高危 CRA 患者。在此过程中，会采集活检样本进行常规组织学诊断，但较差的病理形态学敏感性和特异性极大地限制了诊断准确性。不幸的是，目前尚无可靠的分子标准可预测 CRA 向 CRC 的潜在发展。通过 Affymetrix 技术确定了正常结直肠黏膜（NOR）、CRA 和不同 Dukes' 阶段 CRC 活检标本的基因表达谱，这些标本代表了 CRA 向 CRC 序列的逐步进展。通过定量实时 PCR（qRT-PCR）和免疫组织化学（IHC）进一步分析了代表性调节基因。CRC 与 CRA 和 CRA 与 NOR 的差异表达特征的交集分析允许鉴定出 463 个探针集（psets）的中间特征，这些探针集标志着 NOR->CRA->CRC 的进展。该特征代表了用于高危 CRA 早期诊断的候选标志物的储存库，从而允许及时进行治疗干预和更具选择性的治疗。还确定了另外 279 个指向从 CRA 到 CRC 的恶性转化的 CRC 特异性 psets，这些可能代表 CRC 的潜在治疗靶点。通过 qRT-PCR 和从 463 个 psets 中随机选择的 4 个基因集的 IHC 分析进一步证实了结果的可靠性。
