Advances in high-throughput transcriptomic analysis have revealed abundant RNA post-transcriptional processing mechanisms, including IPA. Interrogating large-scale RNAseq data sets from the TCGA cohort, we provided a systemic view of the IPA landscape in human cancer. We demonstrated a strong pan-cancer pattern of aberrent IPAs and IPA-regulated genes. These pan-cancer turmor-enriched IPA genes are enriched in functional pathways such as DNA repair, suggesting that dysregulated IPAs are involved in accumulation of somatic mutations in human tumors. This concept is supported by our observations that many IPAs are positively correlated with patient tumor mutation burden. In addition, expression of turmor-enriched IPA isoforms is associated with patients’ clinical characteristics such as survival, immune profiles, stage, subtype, sex, and race, suggesting the importance of IPA isoform independent of gene expression (the sum of all isoforms). Our analysis identified 22,260 detectable IPA sites, most of which showed a consistent expression pattern across 33 cancer types. Pan-cancer IPAs have higher usage levels than others, which is reminiscent of features of protein-coding genes and eRNAs -- the housekeeping genes and pan-cancer eRNAs are generally expressed at high levels compared with tissue-specific genes 80 and eRNAs 81, respectively. Tumor cells express transcripts with systematically shorter 3′ UTRs compared to normal cells  by selecting the proximal polyadenylation sites in 3’UTR; many oncogenes are upregulated through this mechanism by escaping regulatory miRNA-mediated repression 10,13,82 . We observed numerous tumor-enriched and depleted IPA genes in each tumor (compared to the paired normal tissues). Tumors also tended to express IPAtruncated isoforms; more samples had a global IPA-related early transcriptional termination (n = 460 and 230, respectively). Unlike 3’UTR-APA, which mainly functions in oncogenes, we found that pan-cancer tumor-enriched IPA genes were largely associated with DNA repair pathways, and tumor-depleted IPA genes were associated with cancer hallmark signatures such as EMT and E2F targets.

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