Human splicing related genes localize within genomic regions frequently re-arranged in cancer

Alex K Joseph, Paul R Hoban
Human Disease and Genomics Group, Institute of Science and Technology in Medicine, Keele University, University Hospital of North Staffordshire, Hartshill, Stoke-on-Trent, ST4 7QB, United Kingdom

Pre-mRNA splicing is a tightly regulated process in gene expression, with alternative splicing providing functional diversity of genes in higher eukaryotes. Numerous examples of aberrant splicing events and deregulated expression of splicing factors have been described in tumors, suggesting that the process of splicing is deregulated in cancer. Chromosome rearrangements in the form of amplification, deletion or translocation, are common in tumors. In this study we have examined whether genes associated with the splicing process are located in regions of genomic re-arrangement in cancer. We first identified 195 splicing related genes (SRG) through their functional annotation in the NCBI Gene database and studied their genomic distribution according to their chromosomal localization given in Ensemble. We found that SRGs are non-randomly distributed in the human genome, with chromosomes 1 and 19 having the highest number of SRGs compared to others. After normalizing for the variation in chromosomal length, we found that the frequency of SRGs observed in chromosome 19 is almost 6 times the average found in the genome. Interestingly, we identified several clusters of SRGs, 4 on chromosome 19, 3 on chromosome 1 and the rest were distributed on 2p13, 5q35, 6p21, 11q13, 12q24 and 16q22. We then analyzed the reports in the Mitelman Database of Recurrent Chromosome Aberrations in Cancer (Cancer Genome Anatomy Project at NCBI) and found that all of the SRG-clusters identified were localized in regions of chromosomal re-arrangements commonly reported across a variety of cancers. We found that specific clusters were more commonly associated with gene amplification whilst others were more associated with chromosomal deletion, suggesting that the expression of specific SRGs within these clusters maybe preferentially amplified or lost in tumors. In support of this finding, analysis of the published literature showed that 3 out of 4 SRGs found to be overexpressed in ovarian tumors, localize to the specific SRG-clusters found to be amplified in this study. In summary our data suggests that genomic re-arrangements in cancer may result in deregulated expression of SRGs, leading to the aberrant splicing that contribute to the clonal evolution of tumors. The localization of specific SRG clusters to genomic regions of amplification or deletion in tumors raises the question whether SRGs are the targets of these chromosomal re-arrangements.