揭示大肠癌综合性分子特性

导读：Nature杂志以开放文章的形式在线报道,众多科学家联手对结直肠癌的分子特点进行了一次综合深入的研究，获得了大量的有用信息。

7月18日，Nature杂志以开放文章的形式在线报道,众多科学家联手对结直肠癌的分子特点进行了一次综合深入的研究，获得了大量的有用信息。

为研究大肠癌的体细胞改变，研究者对276个肿瘤样本的外显子组序列，DNA拷贝数，启动子甲基化状态和信使RNA和microRNA表达进行了基因组规模的分析。

这些样本中的一部分（97例）低深度覆盖全基因组测序。结果发现，16％的大肠癌存在高度的突变：这些样本的四分之三具有预料中的高度微卫星DNA不稳定，通常伴有高甲基化和MLH1的沉默，四分之一具有体细胞错配修复基因和聚合酶ε（POLE）的突变。

剔除含有高度基因突变的那部分肿瘤病例，科学家发现结肠癌和直肠癌基因组的改变有相当类似的模式。二十四个基因显著突变，除了预期的APC，TP53，Smad4、PIK3CA和KRAS突变，研究者还发现，ARID1A，SOX9和FAM123B频繁的突变。

发生经常拷贝数改变的基因包括，潜在的药物靶点ErbB2的扩增和新发现的IGF2基因的扩增。经常发生的染色体易位包括，NAV2的Wnt信号通路成员TCF7L1融合。

总之，本研究发现了一些新的侵袭性的大肠癌的标志物，以及MYC指导的转录激活和抑制在结直肠癌中的重要作用。（生物谷bioon.com）

doi:10.1016/j.cell.2011.10.017
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Comprehensive molecular characterization of human colon and rectal cancer

To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase ε (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include the fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.