UCLA researchers from the Department of Integrative Biology and Physiology have developed a novel method to identify rare 3’ UTR variants that regulate mRNA abundance, with potential applications in predicting cancer patient survival.
BACKGROUND: Non-coding genetic variants play a significant role in diseases such as cancer yet identifying those that increase disease susceptibility has been challenging. Genome-wide association studies (GWAS) have linked certain DNA regions to disease, but they often miss rare variants. Researchers have identified that 3’ untranslated regions (UTRs), which are important in gene regulation, are enriched for non-coding variants. While some of these variants have been characterized, these studies have primarily focused on common genetic variants. As a result, there is a growing demand to investigate the role of non-coding rare 3’ UTR variants, particularly in the context of human disease.
INNOVATION: Researchers at UCLA under the leadership of Dr. Xinshu Xiao have developed a novel massively parallel screen for 3’ UTR variants (MapUTR) to identify rare 3’ UTR variants regulating mRNA abundance post-transcriptionally. Using this approach, they (i) identified rare 3’ UTR variants from the Genome Aggregation Database, (ii) cloned DNA oligonucleotides containing these variants into a plasmid library, (iii) introduced the plasmid library into human cell lines, and (iv) extracted RNA from cells for RNA-sequencing and analysis. MapUTR successfully captured the impact of rare genetic variants on mRNA abundance, revealing that many were functional and enriched in microRNA or protein-binding sites. To evaluate the significance of the rare MapUTR variants, researchers performed gene ontology enrichment analysis and found that many of the genes were associated with cancer. Further investigation using the Catalogue of Somatic Mutations in Cancer showed that numerous cancer driver genes harbored functional 3’ UTR variants. To evaluate clinical relevance, UCLA researchers developed untranslated tumor burden (uTMB), a novel metric quantifying the number of functional MapUTR variants in tumor samples. Using data from The Cancer Genome Atlas, they revealed that a higher uTMB was significantly associated with shorter progression in lung squamous cell carcinoma and head neck squamous cell carcinoma. In summary, UCLA researchers developed MapUTR, a powerful tool to study non-coding genetic variants and discover mutations that alter gene expression in cancer cells, which can be used to predict patient survival outcomes.
POTENTIAL APPLICATIONS:
ADVANTAGES:
DEVELOPMENT-TO-DATE: UCLA researchers have developed an in vitro method to identify rare non-coding genetic variants in the 3’ UTR. The knowledge gained from this method can be applied to cancer samples and has the potential to predict cancer patient survival.
Related Papers (from the inventors only): Fu, T., Amoah, K., Chan, T.W. et al. Massively parallel screen uncovers many rare 3′ UTR variants regulating mRNA abundance of cancer driver genes. Nat Commun 15, 3335 (2024). https://doi.org/10.1038/s41467-024-46795-7
Keywords: Non-coding genetic variant, 3’ UTR, MapUTR, rare genetic variant, clone, RNA-sequencing, microRNA, mutation, gene expression, somatic, uTMB, lung squamous cell carcinoma, head neck squamous cell carcinoma, screening assays