Molecular, Cellular and Integrative Physiology Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Nat Commun. 2024 Apr 18;15(1):3335. doi: 10.1038/s41467-024-46795-7.
Understanding the function of rare non-coding variants represents a significant challenge. Using MapUTR, a screening method, we studied the function of rare 3' UTR variants affecting mRNA abundance post-transcriptionally. Among 17,301 rare gnomAD variants, an average of 24.5% were functional, with 70% in cancer-related genes, many in critical cancer pathways. This observation motivated an interrogation of 11,929 somatic mutations, uncovering 3928 (33%) functional mutations in 155 cancer driver genes. Functional MapUTR variants were enriched in microRNA- or protein-binding sites and may underlie outlier gene expression in tumors. Further, we introduce untranslated tumor mutational burden (uTMB), a metric reflecting the amount of somatic functional MapUTR variants of a tumor and show its potential in predicting patient survival. Through prime editing, we characterized three variants in cancer-relevant genes (MFN2, FOSL2, and IRAK1), demonstrating their cancer-driving potential. Our study elucidates the function of tens of thousands of non-coding variants, nominates non-coding cancer driver mutations, and demonstrates their potential contributions to cancer.
理解罕见非编码变异的功能是一项重大挑战。我们使用 MapUTR 这一筛选方法，研究了影响转录后 mRNA 丰度的罕见 3'UTR 变异的功能。在 17301 个罕见的 gnomAD 变异中，平均有 24.5%是有功能的，其中 70%与癌症相关基因有关，许多与关键的癌症途径有关。这一观察结果促使我们对 11929 个体细胞突变进行了检测，在 155 个癌症驱动基因中发现了 3928 个（33%）有功能的突变。功能性 MapUTR 变异富集在 microRNA 或蛋白质结合位点，可能是肿瘤中基因表达异常的基础。此外，我们引入了未翻译的肿瘤突变负担（uTMB），这一衡量标准反映了肿瘤中体细胞功能性 MapUTR 变异的数量，并展示了其在预测患者生存方面的潜力。通过 Prime 编辑，我们对三个与癌症相关基因（MFN2、FOSL2 和 IRAK1）中的变异进行了特征分析，证明了它们的致癌潜力。我们的研究阐明了数万个非编码变异的功能，提名了非编码的癌症驱动突变，并展示了它们对癌症的潜在贡献。
