Loss of CDX2 expression and microsatellite instability are prominent features of large cell minimally differentiated carcinomas of the colon
Loss of CDX2 expression and microsatellite instability are prominent features of large cell minimally differentiated carcinomas of the colon
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DOI：
10.1016/s0002-9440(10)63074-x
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发表时间：
2001-12-01
影响因子：
6
通讯作者：
Fearon, ER
中科院分区：
文献类型：
--
作者：
Hinoi, T;Tani, M;Fearon, ER
大多数大肠癌为中分化至高分化腺癌，主要或完全由被高柱状细胞排列的腺体组成。我们已经确定了一组分化差的结肠癌亚群，其具有独特的组织病理学表现，我们将其称为大细胞低分化癌（LCMDCs）。这些肿瘤可能包括一组先前被其他人描述为髓样腺癌的分化差的癌。为了更好地理解这些不常见肿瘤的发病机制，我们将15例LCMDCs的分子特征与25例结肠分化腺癌（DACs）的分子特征进行了比较。对肿瘤进行了检查，以确定在典型结直肠癌中常见的改变，包括p53和β -连环蛋白免疫反应性增加、K - ras基因突变、微卫星不稳定性以及5q、17p和18q染色体上标记的杂合性缺失。此外，通过免疫组织化学对肿瘤进行CDX2评估，CDX2是一种同源盒蛋白，其在正常成人组织中的表达仅限于肠和结肠上皮。在15例LCMDCs中有13例（87%）注意到CDX2表达显著降低或缺失，而25例DACs中只有1例（4%）显示CDX2表达降低（P < 0.001）。15例LCMDCs中有9例（60%）具有高频微卫星不稳定性表型，但25例DACs中只有2例（8%）具有高频微卫星不稳定性表型（P = 0.002）。我们的研究结果支持LCMDCs的分子发病机制不同于大多数DACs的这一假设。CDX2改变和DNA错配修复缺陷在LCMDCs的发展中具有特别突出的作用。
Most large bowel cancers are moderately to well-differentiated adenocarcinomas comprised chiefly or entirely of glands lined by tall columnar cells. We have identified a subset of poorly differentiated colon carcinomas with a distinctive histopathological appearance that we term large cell minimally differentiated carcinomas (LCMDCs). These tumors likely include a group of poorly differentiated carcinomas previously described by others as medullary adenocarcinomas. To better understand the pathogenesis of these uncommon neoplasms, we compared molecular features of 15 LCMDCs to those present in 25 differentiated adenocarcinomas (DACs) of the colon. Tumors were examined for alterations commonly seen in typical colorectal carcinomas, including increased p53 and beta -catenin immunoreactivity, K-ras gene mutations, microsatellite instability, and loss of heterozygosity of markers on chromosomes 5q, 17p, and 18q. In addition, tumors were evaluated by immunohistochemistry for CDX2, a homeobox protein whose expression in normal adult tissues is restricted to intestinal and colonic epithelium. Markedly reduced or absent CDX2 expression was noted in 13 of 15 (87%) LCMDCs, whereas only 1 of the 25 (4%) DACs showed reduced CDX2 expression (P < 0.001). Nine of 15 (60%) LCMDCs had the high-frequency microsatellite instability phenotype, but only 2 of 25 (8%) DACs had the high-frequency microsatellite instability phenotype (P = 0.002). Our findings provide support for the hypothesis that the molecular pathogenesis of LCMDCs is distinct from that of most DACs. CDX2 alterations and DNA mismatch repair defects have particularly prominent roles in the development of LCMDCs.