Cancer and Immunogenetics Laboratory, The Weatherall Institute of Molecular Medicine, University of Oxford, The John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom.
Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):21058-63. doi: 10.1073/pnas.1015604107. Epub 2010 Nov 19.
Replication error deficient (RER+) colorectal cancers are a distinct subset of colorectal cancers, characterized by inactivation of the DNA mismatch repair system. These cancers are typically pseudodiploid, accumulate mutations in repetitive sequences as a result of their mismatch repair deficiency, and have distinct pathologies. Regulatory sequences controlling all aspects of mRNA processing, especially including message stability, are found in the 3'UTR sequence of most genes. The relevant sequences are typically A/U-rich elements or U repeats. Microarray analysis of 14 RER+ (deficient) and 16 RER- (proficient) colorectal cancer cell lines confirms a striking difference in expression profiles. Analysis of the incidence of mononucleotide repeat sequences in the 3'UTRs, 5'UTRs, and coding sequences of those genes most differentially expressed in RER+ versus RER- cell lines has shown that much of this differential expression can be explained by the occurrence of a massive enrichment of genes with 3'UTR T repeats longer than 11 base pairs in the most differentially expressed genes. This enrichment was confirmed by analysis of two published consensus sets of RER differentially expressed probesets for a large number of primary colorectal cancers. Sequence analysis of the 3'UTRs of a selection of the most differentially expressed genes shows that they all contain deletions in these repeats in all RER+ cell lines studied. These data strongly imply that deregulation of mRNA stability through accumulation of mutations in repetitive regulatory 3'UTR sequences underlies the striking difference in expression profiles between RER+ and RER- colorectal cancers.
复制错误缺陷（RER+）结直肠癌是结直肠癌的一个独特亚型，其特征是 DNA 错配修复系统失活。这些癌症通常为假二倍体，由于其错配修复缺陷而在重复序列中积累突变，并且具有独特的病理学特征。控制 mRNA 处理各个方面的调节序列，特别是包括消息稳定性，存在于大多数基因的 3'UTR 序列中。相关序列通常是 A/U 丰富元件或 U 重复序列。对 14 个 RER+（缺陷）和 16 个 RER-（熟练）结直肠癌细胞系的微阵列分析证实了表达谱的显著差异。对在 RER+与 RER-细胞系中差异表达最显著的基因的 3'UTR、5'UTR 和编码序列中单核核苷酸重复序列的发生率进行分析表明，这种差异表达的大部分可以通过发生大量富集来解释具有 3'UTR T 重复的基因，这些重复长于 11 个碱基对，在差异表达最显著的基因中。这一富集通过对大量原发性结直肠癌的两个已发表的 RER 差异表达探针集的共识集进行分析得到了证实。对一组差异表达最显著的基因的 3'UTR 进行序列分析表明，在所研究的所有 RER+细胞系中，它们都在这些重复序列中存在缺失。这些数据强烈表明，通过在重复的调节 3'UTR 序列中积累突变导致的 mRNA 稳定性失调，是 RER+和 RER-结直肠癌之间表达谱显著差异的基础。
