Abstract 3979: Ethnic polymorphisms in the GGAA microsatellite response element of key Ewing's sarcoma EWS/FLI-target genes

Abstract

Abstract Study Rationale: Unlike other cancer models, the risk factors predisposing patients to the development of Ewing's sarcoma and predicting subsequent disease behavior are largely unknown. Interestingly, the incidence of Ewing's sarcoma is highest in populations of European descent, which is 10X higher than the incidence observed in those of African descent. Furthermore, cure rates and overall survival are significantly worse in patients of African descent. Recently, it has been shown that the EWS/FLI fusion product selectively binds to a (GGAA)n microsatellite response element embedded within the promoter region of key EWS/FLI-target oncogenes. An increasing number of these repeats also appears to positively affect DNA binding and gene activation. We hypothesize that differences in polymorphic GGAA microsatellites within the promoter regions of key EWS/FLI-target genes may exist in African and European populations, contributing to observed differences in Ewing's sarcoma incidence and outcomes. Methods: Genomic DNA samples were obtained from 100 subjects each of African and European descent. The microsatellite regions within the promoter elements of two key EWS/FLI target genes (NR0B1 and CAV1) were PCR amplified, cloned and sequenced. Microsatellite sequences were analyzed and the overall length of the microsatellite, the total number of GGAA repeats and the maximal number of consecutive repeats were quantified. Data was statistically interpreted using a comparative two-tailed t-test. Results: Measurements of the CAV1 microsatellite response element were quite similar for both African and European subjects. In sharp contrast, marked inter-ethnic variation was observed for the NR0B1 GGAA microsatellite response element. African samples had a significantly longer GGAA microsatellite, a greater number of total (GGAA)n repeats and longer consecutive (GGAA)n repeats (p<0.0001). Conclusions: These data demonstrate a marked inter-ethnic variation in the genetic constitution of the Ewing's sarcoma EWS/FLI-response element within the NR0B1 promoter. Given the epidemiological differences of Ewing's sarcoma susceptibility and disease outcome in these divergent populations and the importance of NR0B1 dysregulation in Ewing's sarcoma oncogenesis, this novel finding warrants further functional investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3979. doi:1538-7445.AM2012-3979