Department of Pathology, University of California San Diego, San Diego, CA 92103, USA.
Int J Oncol. 2010 Sep;37(3):707-18. doi: 10.3892/ijo_00000720.
Accumulating evidence suggests that colorectal cancer (CRC) should be viewed as a heterogeneous disease, with proximal and distal CRCs showing multiple biological and clinical differences. The aim of this study was to develop a clinicopathological, molecular and protein profile for CRCs based on their region and thus providing insight into their heterogeneity. CRC patients (n=399) were evaluated for clinicopathologic and molecular features including K-RAS, BRAF and MSI status. Tumors were also screened for expression of 50 immunohistochemical markers linked to major signaling pathways involved in tumor-progression or immune response. Proximally located tumors show significantly larger tumor size, higher T-stage, higher tumor grade and more frequent mucinous histologic subtype compared to the distal colon and rectum. The frequency of BRAF mutation and MSI-high phenotype were significantly higher in proximal colon cancers. There is a significant difference in regional expression of 10 tumor-associated markers (CDX2, CD44v6, CD44s, TOPK, nuclear beta-catenin, pERK, APAF-1, E-cadherin, p21 and bcl2) and 4 immune response markers (CD68, CD163, FoxP3 and TIA-1). In multivariate analysis CD44s, CD44v6, nuclear beta-catenin and CD68 expression was found to best discriminate left- versus right-sided colon cancers. Tumor diameter, pT stage and MSI status best distinguish right-sided colon cancers from rectal cancers and pT stage and E-cadherin best discriminate left-sided colon cancers and rectal cancers. These data along with existing evidence for the presence of distinct regional embryological origin and gene expression profile are highly supportive of the concept that proximal and distal CRCs are distinct clinicopathologic entities.
越来越多的证据表明，结直肠癌（CRC）应被视为一种异质性疾病，近端和远端 CRC 表现出多种生物学和临床差异。本研究旨在根据 CRC 的部位建立一种临床病理、分子和蛋白图谱，从而深入了解其异质性。对 399 例 CRC 患者进行了临床病理和分子特征评估，包括 K-RAS、BRAF 和 MSI 状态。还对肿瘤进行了 50 种与肿瘤进展或免疫反应相关的主要信号通路相关的免疫组化标志物表达筛选。与远端结肠和直肠相比，近端肿瘤的肿瘤大小明显更大，T 分期更高，肿瘤分级更高，粘液组织学亚型更常见。BRAF 突变和 MSI-高表型在近端结肠癌中的频率明显更高。10 种肿瘤相关标志物（CDX2、CD44v6、CD44s、TOPK、核 β-连环蛋白、pERK、APAF-1、E-cadherin、p21 和 bcl2）和 4 种免疫反应标志物（CD68、CD163、FoxP3 和 TIA-1）的区域表达存在显著差异。多变量分析发现，CD44s、CD44v6、核 β-连环蛋白和 CD68 的表达最能区分左、右侧结肠癌。肿瘤直径、pT 分期和 MSI 状态最能区分右侧结肠癌和直肠癌，pT 分期和 E-cadherin 最能区分左侧结肠癌和直肠癌。这些数据以及存在的不同区域胚胎起源和基因表达谱的证据，高度支持近端和远端 CRC 是不同的临床病理实体的概念。
