Comprehensive characterization of somatic variants associated with intronic polyadenylation in human cancers

Abstract

Somatic single nucleotide variants (SNVs) in cancer genome affect gene expression through various mechanisms depending on their genomic location. While somatic SNVs near canonical splice sites have been reported to cause abnormal splicing of cancer-related genes, whether these SNVs can affect gene expression through other mechanisms remains an open question. Here, we analyzed RNA sequencing and exome data from 4,998 cancer patients covering ten cancer types and identified 152 somatic SNVs near splice sites that were associated with abnormal intronic polyadenylation (IPA). IPA-associated somatic variants favored the localization near the donor splice sites compared to the acceptor splice sites. A proportion of SNV-associated IPA events overlapped with premature cleavage and polyadenylation events triggered by U1 small nuclear ribonucleoproteins (snRNP) inhibition. GC content, intron length and polyadenylation signal were three genomic features that differentiated between SNV-associated IPA and intron retention. Notably, IPA-associated SNVs were enriched in tumor suppressor genes (TSGs), including the well-known TSGs such as PTEN and CDH1 with recurrent SNV-associated IPA events. Minigene assay confirmed that SNVs from PTEN, CDH1, VEGFA, GRHL2, CUL3 and WWC2 could lead to IPA. This work reveals that IPA acts as a novel mechanism explaining the functional consequence of somatic SNVs in human cancer.

RNA-seq analysis, targeted long-read sequencing, and in silico prediction to unravel pathogenic intronic events and predict the regulatory mechanisms underlying complex splicing abnormalities in patients with dystrophinopathy

“…S3a-c). Alteration of a 5' splice site, or a weak 5' splice site in a large subsequent intron, tends to activate intronic polyadenylation (Rani et al 2020;Zhao et al 2021). These reports and our results suggest that disruption of the recursive splice site could be associated with activation of the intronic polyadenylation signal.…”

Intergenic splicing-stimulated transcriptional readthrough is suppressed by nonsense-mediated mRNA decay in Arabidopsis

“…Intronic polyadenylation (IPA) occurs inside an intron of a gene comprising of a single protein-coding ORF and may expand protein diversity by producing a truncated one [36][37][38] . IPA events in humans are associated with diseases like cancer 37,38 .…”

“…Intronic polyadenylation (IPA) occurs inside an intron of a gene comprising of a single protein-coding ORF and may expand protein diversity by producing a truncated one [36][37][38] . IPA events in humans are associated with diseases like cancer 37,38 . In Arabidopsis, it has been reported that hypoxia stress increases the number of mRNAs with IPA and the abnormal mRNAs with IPA may be relatively unstable 36 .…”

Expression Analysis, Molecular Characterization and Prognostic Evaluation on TMED4 and TMED9 Gene Expression in Glioma

“…The co-expression analysis revealed that TMED4 gene is highly co-expressed with TYW1 gene in LGG tissues and NUDCD3 gene in GBM tissues ( Figure 9 ). TYW1 overexpression and mutations are associated with leukemia and breast cancer prognosis [63,64]. NUDCD3 overexpression is also linked to the poor prognosis of cervical cancer patients [65].…”