Putative cis-regulatory drivers in colorectal cancer

摘要

这篇论文对与结肠直肠癌的肿瘤发生相关的调控环境中的转录组改变和变化做了一个全面综述。通过对来自结肠直肠癌患者的103个相匹配的肿瘤和正常结肠粘膜样本进行RNA测序和对等位基因特异性表达进行研究,本文作者发现,生殖系基B型仍然是肿瘤中的等位基因表达的重要决定因素,同时他们也识别出在结肠直肠癌中有过多体细胞顺式调控效应的71个基因,这说明它们起癌症驱动因子的作用。他们识别出了新的"表达量化性状位点"(eQTLs),其中36%是结肠直肠癌独有的。另有证据表明,肿瘤特异性eQTL基因构成来自生殖系的癌症调控驱动因子。%The cis-regulatory effects responsible for cancer development have not been as extensively studied as the perturbations of the protein coding genome in tumorigenesis. 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.