Seshimo I, Yamamoto H, Mishima H, Kurata A, Suzuki R, Ezumi K, Takemasa I, Ikeda M, Fukushima T, Tsujinaka T, Sekimoto M, Kikkawa N, Takenoshita S, Monden M
Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
J Exp Clin Cancer Res. 2006 Sep;25(3):433-42.
Poorly differentiated adenocarcinoma (Por) and signet-ring cell carcinoma (Sig) are rare but highly malignant types of colorectal cancer. To explore their genetic backgrounds we investigated TGF-beta type II receptor (TGF-beta RII) and SMAD4 in the TGF-beta signaling pathway, and to identify their mutator phenotype we examined microsatellite instability (MSI) status. Loss of SMAD4 expression was significantly more frequent in Por (12 of 38; 31%) and Sig (4 of 5; 80%) tumors than in well (Well) and moderately differentiated (Mod) carcinomas (p = 0.04, 0.003, respectively). Mutation of the SMAD4 gene was detected in 2 of 26 Por tumors. MSI was positive in 14 of the 38 Por tumors and in 1 of the 5 Sig tumors, but in none of the Well or Mod tumors examined. We also found mutation of TGF-beta RII, a putative target of MSI, in 10 of 35 Por tumors (28.6%), but in none of 3 Sig tumors. As a whole, about 50% of the Por tumors and 80% of the Sig tumors showed abnormalities of either TGF-beta RII or SMAD4 expression. This suggests that disruption of the TGF-beta signaling pathway may play a central role in the pathogenesis of Por and Sig tumors of the colorectum.
低分化腺癌（Por）和印戒细胞癌（Sig）是罕见但恶性程度很高的结直肠癌类型。为了探究它们的基因背景，我们研究了转化生长因子β（TGF-β）信号通路中的Ⅱ型TGF-β受体（TGF-βRII）和SMAD4，并且为了确定它们的错配修复缺陷表型，我们检测了微卫星不稳定性（MSI）状态。与高分化（Well）和中分化（Mod）癌相比，SMAD4表达缺失在Por肿瘤（38例中的12例；31%）和Sig肿瘤（5例中的4例；80%）中明显更常见（p值分别为0.04和0.003）。在26例Por肿瘤中的2例检测到SMAD4基因的突变。38例Por肿瘤中的14例以及5例Sig肿瘤中的1例MSI呈阳性，但在所检测的高分化或中分化肿瘤中均未发现MSI阳性。我们还在35例Por肿瘤中的10例（28.6%）检测到MSI的假定靶点TGF-βRII的突变，但在3例Sig肿瘤中均未检测到。总体而言，约50%的Por肿瘤和80%的Sig肿瘤显示出TGF-βRII或SMAD4表达异常。这表明TGF-β信号通路的破坏可能在结直肠癌的Por和Sig肿瘤发病机制中起核心作用。
