Population genetics and the role of common variation in EWSR1 translocations in Ewing’s Sarcoma

Nick Orr, Sharon Savage, Gilles Thomas, Stephen Chanock

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Ewing’s Sarcoma (ES) is a rare sarcoma of children and young adults that is notable for a substantial difference in incidence between individuals of Caucasian background and African background. Nearly all ES tumors have a signature translocation with the fusion of the 5’ end of EWSR1 with the 3’ end of FLI1. We have previously observed that the EWSR1 breakpoint region is highly conserved, suggesting that it may be of structural or functional significance. We hypothesize that population-specific factors could contribute to the molecular mechanism underlying ES and we are using population genetics to investigate differences that could influence susceptibility to the ES translocation.

In order to characterize the local sequence, we have conducted an extensive re-sequence analysis of the breakpoints regions, EWSR1A and EWSR1B and extended the analysis across the EWSR1 gene in the SNP500Cancer population (Packer BR, et al. Nucleic Acids Res. 2006 Jan 1;34 D617-21); this is comprised of three genetically diverse and one admixed ethnic groups. We resequenced approximately 7 Kb of sequence and see neither evidence for increased heterozygosity nor evidence for recent selection in any of the studied populations. A total of 28 SNPs were detected, of which many were population private or singletons. We reconstructed haplotypes using PHASE (Stephens M, et al. Am J Hum Genet. 2001 Apr;68(4):978-89) and detected a total of 32 unique haplotypes. Only 7 of these were observed in more than one population; of these, two exhibited significant differences in population frequency between the Caucasian and African American populations in our study sample. One was observed only in Caucasians and one is significantly increased in Caucasians compared to African Americans (by a factor of greater than 6). By neighborhood tree analysis, these two haplotypes appear to be distinct and not closely related. Additional bio-informatic analyses in HapMapII data suggest that the pattern of linkage disequilibrium is significantly different between populations of Caucasian and West African ancestry and thus provide an opportunity to examine extended haplotypes in ES. Assuming a risk in African Americans 10 times less than for Europeans, we postulate that one or more risk haplotypes could be present. Ongoing analyses are directed at re-sequence analysis of the EWSR1 breakpoint regions and extended haplotypes in tumor/germ-line DNA.
Original languageEnglish
Article number1092
JournalCancer Research
Issue number9-Supplement
Publication statusPublished - 01 May 2007
Event97TH AACR ANNUAL MEETING - Washington DC, United States
Duration: 01 Apr 200605 Apr 2006


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