Aberrant DNA Methylation in Hereditary Nonpolyposis Colorectal Cancer Without Mismatch Repair Deficiency
Aberrant DNA Methylation in Hereditary Nonpolyposis Colorectal Cancer Without Mismatch Repair Deficiency
复制标题
DOI：
10.1053/j.gastro.2010.01.035
复制
发表时间：
2010-05-01
期刊：
影响因子：
29.4
通讯作者：
Llor, Xavier
中科院分区：
文献类型：
--
作者：
Goel, Ajay;Xicola, Rosa M.;Llor, Xavier
背景与目的：大约有一半的家庭，满足阿姆斯特丹标准林奇综合征或遗传性非息肉病性结直肠癌（HNPCC）没有证据的种系错配修复基因突变，定义这种综合征，并导致微卫星不稳定性（MSI）。致癌途径和检测微卫星稳定（MSS）HNPCC肿瘤的最佳诊断方法尚不清楚。我们研究了表观遗传学改变对MSS HNPCC肿瘤发展的贡献。方法：结肠直肠癌分为4组：（1）微卫星稳定的阿姆斯特丹阳性（MSS HNPCC）（N = 22）;（2）林奇综合征癌症（鉴定的错配修复突变）（N = 21）;（3）散发性MSS（N = 92）;和（4）散发性MSI（N = 46）。评估了CACNAG 1、SOCS 1、RUIVX 3、IVEUROG 1、MLH 1和长散布核苷酸元件-1（LINE-1）的甲基化状态。分析KRAS和BRAF突变状态。结果：MSS HNPCC肿瘤显示LINE-1甲基化程度显著低于其他组，LINE-1甲基化是整体甲基化的标志物。虽然大多数MSS HNPCC肿瘤具有一定程度的CpG岛甲基化，但没有一个呈现高甲基化指数。MSS HNPCC肿瘤仅在密码子12中具有KRAS突变，但没有携带V600E BRAF突变。结论：来自阿姆斯特丹阳性无错配修复缺陷患者（MSS HNPCC）的肿瘤具有某些分子特征，包括整体低甲基化，这将其与所有其他结直肠癌区分开来。这些特征可能对肿瘤行为或治疗反应产生重要影响。目前正在进行研究，以进一步评估这些特征的原因和影响。
BACKGROUND & AIMS: Approximately half of the families that fulfill Amsterdam criteria for Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) do not have evidence of the germline mismatch repair gene mutations that define this syndrome and result in microsatellite instability (MSI). The carcinogenic pathways and the best diagnostic approaches to detect microsatellite stable (MSS) HNPCC tumors are unclear. We investigated the contribution of epigenetic alterations to the development of MSS HNPCC tumors. METHODS: Colorectal cancers were divided into 4 groups: (1) microsatellite stable, Amsterdam-positive (MSS HNPCC) (N = 22); (2) Lynch syndrome cancers (identified mismatch repair mutations) (N = 21); (3) sporadic MSS (N = 92); and (4) sporadic MSI (N = 46). Methylation status was evaluated for CACNAG1, SOCS1, RUIVX3, IVEUROG1, MLH1, and long interspersed nucleotide element-1 (LINE-1). KRAS and BRAF mutation status was analyzed. RESULTS: MSS HNPCC tumors displayed a significantly lower degree of LINE-1 methylation, a marker for global methylation, than any other group. Although most MSS HNPCC tumors had some degree of CpG island methylation, none presented a high index of methylation. MSS HNPCC tumors had KRAS mutations exclusively in codon 12, but none harbored V600E BRAF mutations. CONCLUSIONS: Tumors from Amsterdam-positive patients without mismatch repair deficiency (MSS HNPCC) have certain molecular features, including global hypomethylation, that distinguish them from all other colorectal cancers. These characteristics could have an important impact on tumor behavior or treatment response. Studies are underway to further assess the cause and effects of these features.