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

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Listed:
  • Ting Fu

    (University of California, Los Angeles
    University of California, Los Angeles)

  • Kofi Amoah

    (University of California, Los Angeles
    University of California, Los Angeles)

  • Tracey W. Chan

    (University of California, Los Angeles
    University of California, Los Angeles)

  • Jae Hoon Bahn

    (University of California, Los Angeles)

  • Jae-Hyung Lee

    (University of California, Los Angeles
    Kyung Hee University)

  • Sari Terrazas

    (University of California, Los Angeles
    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
    University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles)

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.

Suggested Citation

  • Ting Fu & Kofi Amoah & Tracey W. Chan & Jae Hoon Bahn & Jae-Hyung Lee & Sari Terrazas & Rockie Chong & Sriram Kosuri & Xinshu Xiao, 2024. "Massively parallel screen uncovers many rare 3′ UTR variants regulating mRNA abundance of cancer driver genes," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46795-7
    DOI: 10.1038/s41467-024-46795-7
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    1. Xudong Zou & Zhaozhao Zhao & Yu Chen & Kewei Xiong & Zeyang Wang & Shuxin Chen & Hui Chen & Gong-Hong Wei & Shuhua Xu & Wei Li & Ting Ni & Lei Li, 2025. "Impact of rare non-coding variants on human diseases through alternative polyadenylation outliers," Nature Communications, Nature, vol. 16(1), pages 1-17, December.

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