TY - JOUR T1 - Gene 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/2017/03/02/111856.abstract N2 - We anecdotally observed a novel exon skipping event, which was due to the disruption of an exon splicing enhancer far from the exon intron boundary, when doing CRISPR/Cas9 editing. That made us be interested in the investigation of exon skipping events systematically in large cancer cohorts' datasets from TCGA project and three other published studies. We identified this kind of events in 191 genes with the false positive rate estimated to be around 6%. Among these genes, we recaptured the well-known skipping event of exon 14 in the hepatocyte growth factor receptor (MET) in lung cancer patients. We also observed the same skipping events in both DNA mismatch repair gene MLH1 and renin receptor ATP6AP2 in lung and head and neck cancers although they were previously reported to be causative in inherited colorectal cancer and Parkinson disorder, respectively. In addition, we identified three kinds of novel skipping events of the same exon in the tumor suppressor PTEN in breast cancer. One of them might be able to produce an in frame protein with internal deletion of 128 amino acids affecting the phosphatase and catalytic domain. Most importantly, we discovered the gene fusion between cyclin dependent kinase inhibitor CDKN1A and RAS oncogene related protein RAB44. This gene fusion, accompanied by the exon skipping events within CDKN1A, was merely caused by a single nucleotide variation of a splice site of CDKN1A, contrary to the common knowledge that the gene fusions occur mainly as the result of large scale structural variations. Furthermore, the protein sequence of RAB44 was intact but the expression was activated clearly. Considering the high specificity that RAB44 is not expressed in all types of normal tissues and the relatively high prevalence of this kind of gene fusion in bladder cancer (1%), skin melanoma (1%) and stomach cancer (1/400), diagnosis of subgroups and targeted therapy must be worth further study. ER -