E1AGSTAL5
COSMIC somatic 3′-UTR variants in HeLa cells
This library tested somatic 3′-UTR variants drawn from COSMIC and associated with cancer driver genes. Allele-specific mRNA abundance was measured with episomal MapUTR in HeLa cells.
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 et al.
About this study
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.
Full author list & citation
Ting Fu, Kofi Amoah, Tracey W. Chan, Jae Hoon Bahn, Jae-Hyung Lee, Sari Terrazas, Rockie Chong, Sriram Kosuri, Xinshu Xiao. Massively parallel screen uncovers many rare 3′ UTR variants regulating mRNA abundance of cancer driver genes. 2024-04-18. https://doi.org/10.1038/s41467-024-46795-7
Experiments 5
E3ZESU73J
Known 3′-UTR regulatory motif variants in HEK293 cells
The C3Sp1 library tested three alternative alleles at positions within five known regulatory motif classes in human 3′ UTRs. Reference and alternative constructs were assayed by episomal MapUTR in HEK293 cells.
E62OG6O65
Rare gnomAD/ExAC 3′-UTR variants in HeLa cells
This library tested rare population 3′-UTR alleles from the gnomAD/ExAC collection across cancer-related and other host genes. Allele-specific mRNA abundance was measured with episomal MapUTR in HeLa cells.
E64HYWGGY
Rare gnomAD/ExAC 3′-UTR variants in HEK293 cells
This library tested rare population 3′-UTR alleles from the gnomAD/ExAC collection across cancer-related and other host genes. Allele-specific mRNA abundance was measured with episomal MapUTR in HEK293 cells.
E996HZKW0
Known 3′-UTR regulatory motif variants in HeLa cells
The C3Sp1 library tested three alternative alleles at positions within five known regulatory motif classes in human 3′ UTRs. Reference and alternative constructs were assayed by episomal MapUTR in HeLa cells.
Raw source data 28 files
Original supplemental and deposited inputs retained for this study. Download files individually or together as a ZIP; nested folders are preserved. Source reuse terms apply, and sequencing reads may be omitted.
Download all 28 files (ZIP)geo/GSE232571_C1Sp1.fasta.gzgeo/GSE232571_C1Sp2.fasta.gzgeo/GSE232571_C1Sp3.fasta.gzgeo/GSE232571_C2Sp1.fasta.gzgeo/GSE232571_C2Sp2.fasta.gzgeo/GSE232571_C2Sp3.fasta.gzgeo/GSE232571_C2Sp4.fasta.gzgeo/GSE232571_C3Sp1.fasta.gzgeo/GSE232571_family.soft.gzgeo/GSE232571_filelist.txtgeo/GSE232571_RAW.targeo/GSE232572_C4Sp1.fasta.gzgeo/GSE232572_C4Sp2.fasta.gzgeo/GSE232572_C4Sp3.fasta.gzgeo/GSE232572_family.soft.gzgeo/GSE232572_filelist.txtgeo/GSE232572_RAW.targeo/GSE232573_family.soft.gzgithub/MapUTR_data_README.mdgithub/MapUTR_README.mdgithub/MapUTR_UMI_counts_README.mdREADME.txtsupplementary/41467_2024_46795_MOESM1_Supplementary_Information.pdfsupplementary/41467_2024_46795_MOESM3_Supplementary_File_Description.pdfsupplementary/41467_2024_46795_MOESM4_Supplementary_Data_1.xlsxsupplementary/41467_2024_46795_MOESM5_Supplementary_Data_2.xlsxsupplementary/41467_2024_46795_MOESM7_Supplementary_Data_4.xlsxsupplementary/41467_2024_46795_MOESM9_Source_Data.xlsx