Massively parallel screen uncovers many rare 3′ UTR variants regulating mRNA abundance of cancer driver genes

Ting Fu, Kofi Amoah, Tracey W. Chan, Jae Hoon Bahn, Jae-Hyung Lee, Sari Terrazas, Rockie Chong, Sriram Kosuri and Xinshu Xiao ()
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Ting Fu: University of California, Los Angeles
Kofi Amoah: University of California, Los Angeles
Tracey W. Chan: University of California, Los Angeles
Jae Hoon Bahn: University of California, Los Angeles
Jae-Hyung Lee: University of California, Los Angeles
Sari Terrazas: University of California, Los Angeles
Rockie Chong: University of California, Los Angeles
Sriram Kosuri: University of California, Los Angeles
Xinshu Xiao: University of California, Los Angeles

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46795-7

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