Objective Colorectal cancer (CRC) is a common cancer and a leading cause of cancer deaths. Previous studies have identified a number of key steps in the evolution of CRC but our knowledge of driver mutations in CRC remains incomplete. Recognising the potential of studying different human populations to reveal novel insights in disease pathogenesis, we conducted genomic analysis of CRC in Saudi patients. Design In the discovery phase of the study, we conducted whole genome sequencing of tumour and corresponding germline DNA in 27 patients with CRC. In addition to known driver mutations, we identified three MED12 somatic mutations. In the replication phase, we employed a next-generation sequencing approach to capture and sequence MED12 and other candidate genes in a larger sample of 400 patients with CRC and confirmed the enrichment for recurrent MED12 mutations. Results In order to gain insight into a plausible biological mechanism for the potential role of MED12 mutations in CRC, we studied CRC cell lines that differ substantially in the expression level of MED12, and found the latter to be correlated inversely with transforming growth factor (TGF)-β signalling and directly with apoptosis in response to chemotherapeutic agents. Importantly, these correlations were replicated when MED12 expression was experimentally manipulated. Conclusions Our data expand the recently described role of MED12 as a tumour suppressor in other cancers to include CRC, and suggest TGF-β signalling as a potential mediator of this effect.

中文翻译：

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MED12在中东结直肠癌中反复突变

目的结直肠癌（CRC）是一种常见的癌症，也是癌症死亡的主要原因。先前的研究已经确定了 CRC 演变的许多关键步骤，但我们对 CRC 中驱动突变的了解仍然不完整。认识到研究不同人群以揭示疾病发病机制的新见解的潜力，我们对沙特患者的 CRC 进行了基因组分析。设计 在研究的发现阶段，我们对 27 名 CRC 患者的肿瘤和相应的生殖系 DNA 进行了全基因组测序。除了已知的驱动突变外，我们还确定了三个 MED12 体细胞突变。在复制阶段，我们采用新一代测序方法在 400 名 CRC 患者的更大样本中捕获和测序 MED12 和其他候选基因，并证实了复发性 MED12 突变的富集。结果 为了深入了解 MED12 突变在 CRC 中的潜在作用的合理生物学机制，我们研究了 MED12 表达水平存在显着差异的 CRC 细胞系，并发现后者与转化生长因子 (TGF) 呈负相关。 )-β 信号传导和直接与化疗剂反应的细胞凋亡。重要的是，当 MED12 表达被实验操纵时，这些相关性被复制。结论 我们的数据扩展了最近描述的 MED12 在其他癌症中作为肿瘤抑制因子的作用，包括 CRC、