Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA 98195, USA; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
Cell Rep. 2023 Aug 29;42(8):112840. doi: 10.1016/j.celrep.2023.112840. Epub 2023 Jul 28.
3' untranslated region (3' UTR) somatic mutations represent a largely unexplored avenue of alternative oncogenic gene dysregulation. To determine the significance of 3' UTR mutations in disease, we identify 3' UTR somatic variants across 185 advanced prostate tumors, discovering 14,497 single-nucleotide mutations enriched in oncogenic pathways and 3' UTR regulatory elements. By developing two complementary massively parallel reporter assays, we measure how thousands of patient-based mutations affect mRNA translation and stability and identify hundreds of functional variants that allow us to define determinants of mutation significance. We demonstrate the clinical relevance of these mutations, observing that CRISPR-Cas9 endogenous editing of distinct variants increases cellular stress resistance and that patients harboring oncogenic 3' UTR mutations have a particularly poor prognosis. This work represents an expansive view of the extent to which disease-relevant 3' UTR mutations affect mRNA stability, translation, and cancer progression, uncovering principles of regulatory functionality and potential therapeutic targets in previously unexplored regulatory regions.
3' 非翻译区 (3' UTR) 体细胞突变代表了一个在很大程度上尚未被探索的替代性致癌基因失调途径。为了确定 3' UTR 突变在疾病中的意义，我们在 185 例晚期前列腺肿瘤中鉴定了 3' UTR 体细胞变异，发现了 14497 个在致癌途径和 3' UTR 调节元件中富集的单核苷酸突变。通过开发两种互补的大规模平行报告基因检测，我们测量了数千个基于患者的突变如何影响 mRNA 翻译和稳定性，并鉴定了数百个功能变体，使我们能够定义突变意义的决定因素。我们证明了这些突变的临床相关性，观察到不同变体的 CRISPR-Cas9 内源性编辑增加了细胞应激抗性，并且携带致癌 3' UTR 突变的患者预后特别差。这项工作代表了对与疾病相关的 3' UTR 突变如何影响 mRNA 稳定性、翻译和癌症进展的广泛认识，揭示了在以前未被探索的调节区域中调节功能的原则和潜在的治疗靶点。
