Gene regulatory alterations as cancer drivers
Non-mutational alterations in cancer represent a major, underappreciated, and targetable contributor to cancer pathogenesis. While the role of protein coding mutations has been extensively studied, our knowledge of mechanisms driving differential gene regulation in cancer remains largely unexplored. We have previously demonstrated that somatic mutations within gene regulatory regions can significantly alter the expression of cancer drivers, regulate oncogenic pathways, and provide prognostic information (Feigin, Garvin et al. 2017).
Investigating alternative polyadenylation (APA)
Our current focus is a mutation-independent gene regulatory process, alternative polyadenylation (APA):
- APA generates mRNAs with distinct 3’ ends, frequently resulting in altered 3’-untranslated region (UTR) length.
- Changes in 3’-UTR length can modulate mRNA stability, function or subcellular localization through disruption of miRNA or RNA-binding protein regulation.
- APA factors are frequently dysregulated in cancer and thought to promote tumorigenesis by altering the expression of oncogenes and tumor suppressors.
The first large-scale single tumor type analysis of APA in cancer
In a study published in 2020, we revealed APA signatures associated with poor patient outcome, and uncovered the casein kinase CK1alpha as a novel therapeutic target in PDA (Venkat et al. 2020).
We are now extending this work to understand the mechanisms by which APA factors are dysregulated in cancer, as well as determining the feasibility of targeting APA therapeutically.
Recent publications
Venkat S, Tisdale AA, Schwarz JR, Alahmari AA, Maurer HC, Olive KP, Eng KH and Feigin ME. Alternative polyadenylation drives oncogenic gene expression in pancreatic ducal adenocarcinoma. Genome Research. 2020. doi: 10.1101/gr.257550.119. PMID: 32029502. PMCID: PMC7111527.
Feigin ME, Garvin T, Bailey P, Waddell N, Chang DK, Shuai S, Gallinger S, McPherson JD, Grimmond SM, Khurana E, Stein LD, Biankin AV, Schatz MC, Tuveson DA. Recurrent noncoding regulatory mutations in pancreatic ductal adenocarcinoma. Nat Genet. 2017 Jun;49(6):825-833. doi: 10.1038/ng.3861. Epub 2017 May 8. PMID: 28481342. PMCID: PMC5659388.