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Nature:解析非编码DNA对癌症发生发展的影响

  1. 基因组
  2. 癌症
  3. 非编码DNA

来源:生物谷 2014-07-26 14:45

癌症是由突变引发的疾病,我们从父母身上或强或弱地继承了罹患某些种类癌症的遗传倾向性,此外,在我们整个一生中细胞也积聚新的基因突变。

2014年7月25讯 /生物谷BIOON/--癌症是由突变引发的疾病,我们从父母身上或强或弱地继承了罹患某些种类癌症的遗传倾向性,此外,在我们整个一生中细胞也积聚新的基因突变。

尽管癌症的遗传起源已经研究了很长时间,但研究人员目前还无法测量基因组的非编码区在癌症发生发展过程中的作用。一组来自日内瓦大学(UNIGE)的遗传学家,通过研究大肠癌患者组织,已经成功地解码这个尚未开发,但至关重要的基因组非编码区。他们的研究结果发表在Nature杂志上。

为了更好地了解癌症的发展,科学家们努力寻找可以作为癌症催化剂或触发肿瘤进展的遗传因素(无论是遗传性还是获得性的基因突变)。到现在为止,癌症的遗传基础只是检验基因组的编码区,但是编码区只占基因组的2%。然而,最近的科学研究显示,其他98%非编码区在癌症的发展中也发挥了重要作用。

为了更好地理解该非编码区的作用,Louis-Jeantet教授Emmanouil Dermitzakis和他的团队,研究了大肠肠癌(是最常见,最致命的癌症之一)。利用基因组测序技术,UNIGE遗传学家比较了103例患者健康组织和肿瘤组织之间的RNA,寻找基因组非编码部分影响大肠癌发展的调控元件。

该研究目标是确定获得性突变对癌症的影响。该UNIGE团队识别两类非编码基因突变,对大肠癌的发展产生影响。研究指出:位于非编码基因组中的负责癌症发生和发展的元素,与那些在基因组编码区中发现的癌症调控元素同等重要。因此,分析我们全基因组,而不单单分析其编码区,使我们对于大肠癌基因的认识更全面。(生物谷Bioon.com)

Putative cis-regulatory drivers in colorectal cancer

Halit Ongen,  Claus L. Andersen,  Jesper B. Bramsen,  Bodil Oster,  Mads H. Rasmussen, Pedro G. Ferreira,  Juan Sandoval,  Enrique Vidal,  Nicola Whiffin,  Alexandra Planchon, Ismael Padioleau,  Deborah Bielser,  Luciana Romano,  Ian Tomlinson,  Richard S. Houlston, Manel Esteller,  Torben F. Orntoft  & Emmanouil T. Dermitzakis

The cis-regulatory effects responsible for cancer development have not been as extensively studied as the perturbations of the protein coding genome in tumorigenesis1, 2. To better characterize colorectal cancer (CRC) development we conducted an RNA-sequencing experiment of 103 matched tumour and normal colon mucosa samples from Danish CRC patients, 90 of which were germline-genotyped. By investigating allele-specific expression (ASE) we show that the germline genotypes remain important determinants of allelic gene expression in tumours. Using the changes in ASE in matched pairs of samples we discover 71 genes with excess of somatic cis-regulatory effects in CRC, suggesting a cancer driver role. We correlate genotypes and gene expression to identify expression quantitative trait loci (eQTLs) and find 1,693 and 948 eQTLs in normal samples and tumours, respectively. We estimate that 36% of the tumour eQTLs are exclusive to CRC and show that this specificity is partially driven by increased expression of specific transcription factors and changes in methylation patterns. We show that tumour-specific eQTLs are more enriched for low CRC genome-wide association study (GWAS) P values than shared eQTLs, which suggests that some of the GWAS variants are tumour specific regulatory variants. Importantly, tumour-specific eQTL genes also accumulate more somatic mutations when compared to the shared eQTL genes, raising the possibility that they constitute germline-derived cancer regulatory drivers. Collectively the integration of genome and the transcriptome reveals a substantial number of putative somatic and germline cis-regulatory cancer changes that may have a role in tumorigenesis.

 

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