Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, United States.
Department of Pathology, Case Western Reserve University, Cleveland, United States.
Elife. 2019 Feb 13;8:e40760. doi: 10.7554/eLife.40760.
Commonly-mutated genes have been found for many cancers, but less is known about mutations in cis-regulatory elements. We leverage gains in tumor-specific enhancer activity, coupled with allele-biased mutation detection from H3K27ac ChIP-seq data, to pinpoint potential enhancer-activating mutations in colorectal cancer (CRC). Analysis of a genetically-diverse cohort of CRC specimens revealed that microsatellite instable (MSI) samples have a high indel rate within active enhancers. Enhancers with indels show evidence of positive selection, increased target gene expression, and a subset is highly recurrent. The indels affect short homopolymer tracts of A/T and increase affinity for FOX transcription factors. We further demonstrate that signature mismatch-repair (MMR) mutations activate enhancers using a xenograft tumor metastasis model, where mutations are induced naturally via CRISPR/Cas9 inactivation of prior to tumor cell injection. Our results suggest that MMR signature mutations activate enhancers in CRC tumor epigenomes to provide a selective advantage.
已经发现许多癌症存在常见的基因突变，但对于顺式调控元件的突变了解较少。我们利用肿瘤特异性增强子活性的增加，结合 H3K27ac ChIP-seq 数据的等位基因偏倚突变检测，精确定位结直肠癌（CRC）中的潜在增强子激活突变。对一组遗传多样化的 CRC 标本进行分析表明，微卫星不稳定（MSI）样本在活性增强子中具有很高的插入缺失率。具有插入缺失的增强子显示出正选择的证据，靶基因表达增加，并且亚组具有高度重现性。插入缺失影响 A/T 短同源多聚体序列，并增加 FOX 转录因子的亲和力。我们进一步证明，特征性错配修复（MMR）突变通过使用异种移植肿瘤转移模型来激活增强子，其中通过 CRISPR/Cas9 失活在肿瘤细胞注射前自然诱导突变。我们的结果表明，MMR 特征性突变激活 CRC 肿瘤表观基因组中的增强子，为肿瘤提供选择性优势。
