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来自中山大学附属第六医院，美国华盛达大学Fred Hutchinson肿瘤中心等处的研究人员发现了腺瘤中DNA甲基化状态是控制肿瘤恶性分化的关键机制，这为肿瘤恶变提供了新思路。
这一研究成果公布在Gastroenterology杂志上，文章的第一作者是中山大学附属第六医院骆衍新博士，第一单位为中山大学附属第六医院。骆衍新博士主要从事胃肠道肿瘤的基础发病机制等方面的研究，也进行以手术为主导的临床综合治疗，去年入选
中山大学“****”。
结肠癌指结肠黏膜上皮在环境或遗传等多种致癌因素作用下发生的恶性病变，是世界第三大癌症，虽然过去几十年来，结肠癌的治疗技术取得了长足进步，但其分子病理机制至今仍未被科学家清楚阐明。之前的研究认为，散发性结直肠癌主要由腺瘤发展而来。但最新研究提出，从正常结肠粘膜到腺瘤（息肉）再发展成为腺癌，一般需要经历十几年、甚至几十年的时间。而息肉作为良性病变在肠镜下即可切除，这可以有效地阻断恶性肿瘤的发生。
研究人员分析检测了正常结肠粘膜、腺瘤、腺癌三种组织状态下的基因组DNA甲基化状态及关键基因突变，发现人体结肠DNA甲基化引起的“表观遗传学不稳定性”状态有可能是导致抑癌基因失活、癌基因激活的主要机制。
这项研究发现了腺瘤中DNA甲基化状态是控制肿瘤恶性化分化的关键机制，这为肿瘤恶变提供了新思路。而且研究中发现的关键基因位点，有望成为预测肿瘤是否癌变的生物标记物，从而用以指导合理治疗方案及随访策略的制定。
此外，今年早期的另外一项研究中，来自芝加哥大学的一个研究小组证实，可引起小肠和结肠出现慢性炎症，最终导致癌症的β-catenin激活会以一种持久且有害的方式改变免疫系统。
研究人员发现在患有长期溃疡性结肠炎和结肠癌患者的T细胞中β-catenin水平增高，这表明β-catenin可能是结肠癌的罪魁祸首，详细内容请见Science医学：发现结肠癌的分子祸首。（生物通：万纹）
原文摘要：
Differences in DNA Methylation Signatures Reveal Multiple Pathways of Progression from Adenoma to Colorectal Cancer.
BACKGROUND: & Aims: Genetic and epigenetic alterations contribute to the pathogenesis of colorectal cancer (CRC). There is considerable molecular heterogeneity among colorectal tumors, which appears to arise as polyps progress to cancer. This heterogeneity results in different pathways to tumorigenesis. Although epigenetic and genetic alterations have been detected in conventional tubular adenomas, little is known about how these affect progression to CRC. We compared methylomes of normal colon mucosa, tubular adenomas, and colorectal cancers to determine how epigenetic alterations might contribute to cancer formation.
METHODS: We conducted genome-wide array-based studies and comprehensive data analyses of aberrantly methylated loci in 41 normal colon tissue, 42 colon adenomas, and 64 cancers using HumanMethylation450 arrays.
RESULTS: We found genome-wide alterations in DNA methylation in the non-tumor colon mucosa adjacent to tubular adenomas and cancers. Three classes of cancers and 2 classes of adenomas were identified based on their DNA methylation patterns. The adenomas separated into classes of high-frequency methylation (adenoma-H), and low-frequency methylation (adenoma-L). Within the adenoma-H class a subset of adenomas had mutant KRAS. Additionally, the adenoma-H class had DNA methylation signatures similar to those of cancers with low or intermediate levels of methylation, whereas the adenoma-L class had methylation signatures similar to that of non-tumor colon tissue. The CpGs sites that were differentially methylated in these signatures are located in intragenic and intergenic regions.
CONCLUSIONS: Genome-wide alterations in DNA methylation occur during early stages of progression of tubular adenomas to cancer. These findings reveal heterogeneity in the pathogenesis of colorectal cancer, even at the adenoma step of the process.
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