Ewing sarcoma, a pediatric tumor characterized by EWSR1-ETS fusions, is predominantly observed in populations of European ancestry. We performed a genome-wide association study (GWAS) of 401 French individuals with Ewing sarcoma, 684 unaffected French individuals and 3,668 unaffected individuals of European descent and living in the United States. We identified candidate risk loci at 1p36.22, 10q21 and 15q15. We replicated these loci in two independent sets of cases and controls. Joint analysis identified associations with rs9430161 (P = 1.4 × 10(-20); odds ratio (OR) = 2.2) located 25 kb upstream of TARDBP, rs224278 (P = 4.0 × 10(-17); OR = 1.7) located 5 kb upstream of EGR2 and, to a lesser extent, rs4924410 at 15q15 (P = 6.6 × 10(-9); OR = 1.5). The major risk haplotypes were less prevalent in Africans, suggesting that these loci could contribute to geographical differences in Ewing sarcoma incidence. TARDBP shares structural similarities with EWSR1 and FUS, which encode RNA binding proteins, and EGR2 is a target gene of EWSR1-ETS. Variants at these loci were associated with expression levels of TARDBP, ADO (encoding cysteamine dioxygenase) and EGR2.
Pre-mRNA splicing and polyadenylation are tightly connected to transcription, and transcriptional stimuli and elongation dynamics can affect mRNA maturation. However, whether this regulatory mechanism has a physio/pathological impact is not known. In cancer, where splice variant expression is often deregulated, many mutated oncogenes are transcriptional regulators. In particular, the Ewing sarcoma (EwSa) oncogene, resulting from a fusion of the EWS and FLI1 genes, encodes a well characterized transcription factor. EWS-FLI1 directly stimulates transcription of the CCND1 protooncogene encoding cyclin D1a and a less abundant but more oncogenic splice isoform, D1b. We show that, although both EWS and EWS-FLI1 enhance cyclin D1 gene expression, they regulate the D1b/D1a transcript ratio in an opposite manner. Detailed analyses of RNA polymerase dynamics along the gene and of the effects of an inhibitor of elongation show that EWS-FLI1 favors D1b isoform expression by decreasing the elongation rate, whereas EWS has opposite effects. As a result, the D1b/D1a ratio is elevated in EwSa cell lines and tumors. The endogenous D1b protein is enriched in nuclei, where the oncogenic activity of cyclin D1 is known to occur, and depleting D1b in addition to D1a results in a stronger reduction of EwSa cell growth than depleting D1a only. These data show that elevated expression of a splice isoform in cancer can be due to an alteration of the transcription process by a mutated transcriptional regulator and provide evidence for a physio/pathological impact of the coupling between transcription and mRNA maturation.coregulator ͉ Ewing sarcoma ͉ EWS-FLI1 ͉ polyadenylation ͉ splicing G ene expression in cancer cells is altered at the transcriptional level by many mutated oncogenes acting as transcriptional regulators. A second level of gene expression that is often altered in cancer cells is pre-mRNA splicing. Indeed, most human genes give rise to several transcripts with different exon content because of alternative splicing and alternative cleavage/ polyadenylation sites (1). Genes involved in major cellular programs often give rise to splice isoforms with distinct biological activities and deregulated expression in cancer (2, 3). In some cases, cancer-associated deregulation of alternative splicing arises from mutations within splicing regulatory sequences or from alterations of the expression of splicing factors involved in splicing regulation (2, 3). However, only few splicing factors have been found to be altered in cancer. Moreover, the role of another level of splicing regulation that involves transcriptional regulators has not been investigated yet.It is now widely accepted that pre-mRNA splicing and 3Ј-end maturation are tightly connected to transcription in Metazoans and that transcription impacts RNA processing (4, 5). It has been shown that the recruitment of processing factors and the maturation of pre-mRNAs occur at least in part cotranscriptionally and are enhanced by RNA polymerase II (Pol II) and its phosphorylation (...
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