Transcript fusion between CDKN1A and RAB44 caused by exon skipping like mechanism due to disruption of a splice site

Alternative splicing, and specifically alternative exon inclusion, is one of the best studied mechanisms that create alternative isoforms. In its simplest form, alternative exon inclusion can be represented as exon skipping. Novel exon skipping events can be created through mutation events near and far from splice junctions, and thus may contribute to diseases, such as cancer. We systematically investigated exon skipping events in large cancer cohort datasets from The Cancer Genome Atlas (TCGA) project and three other published studies. We identified similar events in 191 genes with an estimated false positive rate of ~6%. Among these genes, we recaptured a known skipping event in exon 14 of the hepatocyte growth factor receptor (MET) in lung cancer patients. We also observed the similar exon skipping events in a DNA mismatch repair gene MLH1 and a renin receptor ATP6AP2 in lung and head and neck cancers. These exon skipping events were previously reported to be causative in inherited colorectal cancer and Parkinson disorder, respectively. In addition, we identified three novel exon skipping events of the same exon in the tumor suppressor PTEN in breast cancer. One of the events has the potential to produce an in frame protein with an internal deletion of 128 amino acids affecting the phosphatase and catalytic domain. Most importantly, we discovered a transcript fusion between cyclin dependent kinase inhibitor CDKN1A and RAS oncogene related protein RAB44. This transcript fusion, accompanied by the exon skipping events within CDKN1A, was caused only by a single nucleotide variation of a splice site of CDKN1A. Furthermore, the protein sequence of RAB44 was intact but its expression was clearly activated. The strong tissue specificity of RAB44 and the relatively high prevalence of this instance of transcript fusion in bladder cancer (1%), skin melanoma (1%) and stomach cancer (1/400) may warrant further study that could inform subclassifications of these cancers and the development of targeted therapies. Introduction Exon skipping is the most common mode of alternative splicing in mammalian cells. One of the first cases of exon skipping was described due to mutations outside of a splice site in the Dystrophin gene in a Duchenne Muscular Dystrophy (DMD) patient in 1991. After that, several other cases were reported, including FBN1 in Marfan syndrome (MFS), ADA in severe combined immunodeficiency disease (SCID), and HMBS in acute intermittent porphyria (AIP). Valentine postulated that such exon skipping . CC-BY-NC 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/111856 doi: bioRxiv preprint first posted online Mar. 2, 2017;