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Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma
Authors:Postel-Vinay Sophie  Véron Amélie S  Tirode Franck  Pierron Gaelle  Reynaud Stéphanie  Kovar Heinrich  Oberlin Odile  Lapouble Eve  Ballet Stelly  Lucchesi Carlo  Kontny Udo  González-Neira Anna  Picci Piero  Alonso Javier  Patino-Garcia Ana  de Paillerets Brigitte Bressac  Laud Karine  Dina Christian  Froguel Philippe  Clavel-Chapelon Françoise  Doz Francois  Michon Jean  Chanock Stephen J  Thomas Gilles  Cox David G  Delattre Olivier
Affiliation:INSERM, U Génétique et Biologie des Cancers, Institut Curie, Paris, France.
Abstract: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.
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