TY - JOUR T1 - Transcript fusion between CDKN1A and RAB44 caused by exon skipping like mechanism due to disruption of a splice site JF - bioRxiv DO - 10.1101/111856 SP - 111856 AU - Han Sun AU - Jingyan Wu AU - Chenchen Zhu AU - Raeka Aiyar AU - Petra Jakob AU - William Mueller AU - Wu Wei AU - Lars M. Steinmetz Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/03/20/111856.abstract N2 - 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. ER -