7月18日，Nature雜志以開放文章的形式在線報道,眾多科學(xué)家聯(lián)手對結(jié)直腸癌的分子特點進(jìn)行了一次綜合深入的研究，獲得了大量的有用信息,。
為研究大腸癌的體細(xì)胞改變，研究者對276個腫瘤樣本的外顯子組序列,，DNA拷貝數(shù),，啟動子甲基化狀態(tài)和信使RNA和microRNA表達(dá)進(jìn)行了基因組規(guī)模的分析。
這些樣本中的一部分（97例）低深度覆蓋全基因組測序,。結(jié)果發(fā)現(xiàn),，16％的大腸癌存在高度的突變：這些樣本的四分之三具有預(yù)料中的高度微衛(wèi)星DNA不穩(wěn)定，通常伴有高甲基化和MLH1的沉默,，四分之一具有體細(xì)胞錯配修復(fù)基因和聚合酶ε（POLE）的突變,。
剔除含有高度基因突變的那部分腫瘤病例，科學(xué)家發(fā)現(xiàn)結(jié)腸癌和直腸癌基因組的改變有相當(dāng)類似的模式,。二十四個基因顯著突變,，除了預(yù)期的APC，TP53,，Smad4,、PIK3CA和KRAS突變，研究者還發(fā)現(xiàn),，ARID1A,，SOX9和FAM123B頻繁的突變,。
發(fā)生經(jīng)常拷貝數(shù)改變的基因包括,，潛在的藥物靶點ErbB2的擴(kuò)增和新發(fā)現(xiàn)的IGF2基因的擴(kuò)增,。經(jīng)常發(fā)生的染色體易位包括，NAV2的Wnt信號通路成員TCF7L1融合,。
總之,，本研究發(fā)現(xiàn)了一些新的侵襲性的大腸癌的標(biāo)志物，以及MYC指導(dǎo)的轉(zhuǎn)錄激活和抑制在結(jié)直腸癌中的重要作用,。（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.
