1. Massively parallel screen uncovers many rare 3′ UTR variants regulating mRNA abundance of cancer driver genes
- Author
-
Fu, Ting, Amoah, Kofi, Chan, Tracey W, Bahn, Jae Hoon, Lee, Jae-Hyung, Terrazas, Sari, Chong, Rockie, Kosuri, Sriram, and Xiao, Xinshu
- Subjects
Biological Sciences ,Bioinformatics and Computational Biology ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Cancer Genomics ,Biotechnology ,Genetics ,Human Genome ,2.1 Biological and endogenous factors ,Aetiology ,Humans ,3' Untranslated Regions ,RNA ,Messenger ,Mutation ,Oncogenes ,Neoplasms - Abstract
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.
- Published
- 2024