Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma.
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.
INSERM, U Génétique et Biologie des Cancers, Institut Curie, Paris, France.
Sophie
S
Postel-Vinay
Amélie S
AS
Véron
Franck
F
Tirode
Gaelle
G
Pierron
Stéphanie
S
Reynaud
Heinrich
H
Kovar
Odile
O
Oberlin
Eve
E
Lapouble
Stelly
S
Ballet
Carlo
C
Lucchesi
Udo
U
Kontny
Anna
A
González-Neira
Piero
P
Picci
Javier
J
Alonso
Ana
A
Patino-Garcia
Brigitte Bressac
BB
de Paillerets
Karine
K
Laud
Christian
C
Dina
Philippe
P
Froguel
Françoise
F
Clavel-Chapelon
Francois
F
Doz
Jean
J
Michon
Stephen J
SJ
Chanock
Gilles
G
Thomas
David G
DG
Cox
Olivier
O
Delattre
D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D051767:Early Growth Response Protein 2 / Q000235:genetics*; D005602:France; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D016015:Logistic Models; D016017:Odds Ratio; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012512:Sarcoma, Ewing / Q000208:ethnology / Q000235:genetics*
D004268:DNA-Binding Proteins; C497326:EGR2 protein, human; D051767:Early Growth Response Protein 2