A human-specific switch of alternatively spliced isoforms contributes to mutations and tumor recurrence in hepatocellular carcinoma.

Pre-mRNA splicing can contribute to the switch of cell identity that occurs in carcinogenesis. Here, we analyze a large collection of RNA-seq data sets and report that splicing changes in hepatocyte-specific enzymes, such as and , are associated with HCC patients' survival and relapse. The switch of isoforms is an early event in HCC development and is associated with driver mutations in and The switch of isoforms is human-specific and not detectable in other species, including primates. Finally, we show that overexpression of the full-length isoform leads to a higher NAD level, lower DNA-damage response, and slower cell growth in HepG2 cells. The integrative analysis uncovered a mechanistic link between splicing switches, de novo NAD biosynthesis, driver mutations, and HCC recurrence.