Multiple strategies are continuously being explored to expand the drug target repertoire in solid tumors. We devised a novel computational workflow for transcriptome‐wide gene expression outlier analysis that allows the systematic identification of both overexpression and underexpression events in cancer cells. Here, it was applied to expression values obtained through RNA sequencing in 226 colorectal cancer (CRC) cell lines that were also characterized by whole‐exome sequencing and microarray‐based DNA methylation profiling. We found cell models displaying an abnormally high or low expression level for 3533 and 965 genes, respectively. Gene expression abnormalities that have been previously associated with clinically relevant features of CRC cell lines were confirmed. Moreover, by integrating multi‐omics data, we identified both genetic and epigenetic alternations underlying outlier expression values. Importantly, our atlas of CRC gene expression outliers can guide the discovery of novel drug targets and biomarkers. As a proof of concept, we found that CRC cell lines lacking expression of the MTAP gene are sensitive to treatment with a PRMT5‐MTA inhibitor (MRTX1719). Finally, other tumor types may also benefit from this approach.

中文翻译：

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全转录组基因表达异常值分析查明结直肠癌的治疗脆弱性

人们不断探索多种策略来扩大实体瘤的药物靶点库。我们设计了一种用于全转录组基因表达异常值分析的新型计算工作流程，可以系统地识别癌细胞中的过度表达和表达不足事件。在这里，它被应用于通过 RNA 测序获得的 226 个结直肠癌 (CRC) 细胞系的表达值，这些细胞系也通过全外显子组测序和基于微阵列的 DNA 甲基化分析进行了表征。我们发现细胞模型中 3533 个基因和 965 个基因分别表现出异常高或低的表达水平。先前与CRC细胞系的临床相关特征相关的基因表达异常得到证实。此外，通过整合多组学数据，我们确定了异常表达值背后的遗传和表观遗传改变。重要的是，我们的 CRC 基因表达异常值图谱可以指导新药物靶点和生物标志物的发现。作为概念证明，我们发现 CRC 细胞系缺乏表达MTAP基因对 PRMT5-MTA 抑制剂 (MRTX1719) 治疗敏感。最后，其他肿瘤类型也可能受益于这种方法。