Sakamoto Naoto, Terai Takeshi, Ajioka Yoichi, Abe Satoshi, Kobayasi Osamu, Hirai Shu, Hino Okio, Watanabe Hidenobu, Sato Nobuhiro, Shimoda Tadakazu, Fujii Hiroaki
Department of Pathology(II), Juntendo University, Juntendo University School of Medicine, 2-1-1 Hongo, Tokyo 113-8421, Japan.
Oncogene. 2004 Nov 25;23(55):8900-7. doi: 10.1038/sj.onc.1207993.
Flat colorectal tumors, characterized by high-grade dysplasia from early small flat mucosal lesions, exhibit a relatively aggressive clinical behavior and are known for their infrequent K-ras mutations. In this study, we investigated the methylation status of the RASSF1A promoter in association with 3p LOH and K-ras mutations in 48 flat colorectal tumors (39 early carcinomas and nine intramucosal high-grade dysplasias). RASSF1A hypermethylation was detected in 39 of 48 (81.3%) tumors and RASSF1A methylation was also detected in 19 of 39 (49%) normal colonic mucosal tissues. 3p21.3 LOH was detected in 20 of 42 (47.6%) cases, but RASSF1 methylation was detected in cases with LOH (14 cases) and retention of 3p21.3 (20 cases). K-ras mutations were detected in seven of 48 (14.6%) tumors and the concordant occurrence of K-ras mutation and RASSF1A methylation was detected in three of 48 cases (6.3%). Overall, there was a statistically significant mutually exclusive relationship between K-ras mutations and RASSF1A methylation. In conclusion, promoter hypermethylation of RASSF1A is a frequent event and may start early in the background normal mucosa in this tumor type. An alternative cascade of abnormalities in RAS transduction pathways may be responsible for the flat morphology and aggressive nature of flat colorectal neoplasms.
扁平结直肠肿瘤由早期小的扁平黏膜病变发展而来，具有高级别发育异常的特征，表现出相对侵袭性的临床行为，且以K-ras突变罕见而闻名。在本研究中，我们调查了48例扁平结直肠肿瘤（39例早期癌和9例黏膜内高级别发育异常）中RASSF1A启动子的甲基化状态，并将其与3p杂合性缺失（LOH）和K-ras突变相关联。48例肿瘤中有39例（81.3%）检测到RASSF1A高甲基化，39例正常结肠黏膜组织中有19例（49%）也检测到RASSF1A甲基化。42例中有20例（47.6%）检测到3p21.3 LOH，但在发生LOH的病例（14例）和保留3p21.3的病例（20例）中均检测到RASSF1甲基化。48例肿瘤中有7例（14.6%）检测到K-ras突变，48例中有3例（6.3%）检测到K-ras突变与RASSF1A甲基化同时出现。总体而言，K-ras突变与RASSF1A甲基化之间存在统计学上显著的相互排斥关系。总之，RASSF1A启动子高甲基化是一种常见事件，可能在该肿瘤类型的背景正常黏膜中早期就已发生。RAS转导通路中异常的另一种级联反应可能是扁平结直肠肿瘤扁平形态和侵袭性本质的原因。
