title: Integrative genome-wide analysis of the determinants of RNA splicing in kidney renal clear cell carcinoma.
abstract: We present a genome-wide analysis of splicing patterns of 282 kidney renal clear cell carcinoma patients in which we integrate data from whole-exome sequencing of tumor and normal samples, RNA-seq and copy number variation. We proposed a scoring mechanism to compare splicing patterns in tumor samples to normal samples in order to rank and detect tumor-specific isoforms that have a potential for new biomarkers. We identified a subset of genes that show introns only observable in tumor but not in normal samples, ENCODE and GEUVADIS samples. In order to improve our understanding of the underlying genetic mechanisms of splicing variation we performed a large-scale association analysis to find links between somatic or germline variants with alternative splicing events. We identified 915 cis- and trans-splicing quantitative trait loci (sQTL) associated with changes in splicing patterns. Some of these sQTL have previously been associated with being susceptibility loci for cancer and other diseases. Our analysis also allowed us to identify the function of several COSMIC variants showing significant association with changes in alternative splicing. This demonstrates the potential significance of variants affecting alternative splicing events and yields insights into the mechanisms related to an array of disease phenotypes.
authors.affiliation: Computational Biology Center, Memorial Kettering Cancer Center, New York, NY 10044, U.S.A.
authors.forename: Kjong-Van
authors.initials: KV
authors.lastname: Lehmann
authors.forename: André
authors.initials: A
authors.lastname: Kahles
authors.forename: Cyriac
authors.initials: C
authors.lastname: Kandoth
authors.forename: William
authors.initials: W
authors.lastname: Lee
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
authors.forename: Oliver
authors.initials: O
authors.lastname: Stegle
authors.forename: Gunnar
authors.initials: G
authors.lastname: Rätsch
mesh_terms: D017398:Alternative Splicing; D014408:Biomarkers, Tumor / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D019295:Computational Biology; D059472:Exome; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D007438:Introns; D007680:Kidney Neoplasms / Q000235:genetics*; D040641:Quantitative Trait Loci; D012326:RNA Splicing; D017423:Sequence Analysis, RNA
chemical_list: D014408:Biomarkers, Tumor