Variation at 10p12.2 and 10p14 influences risk of childhood B-cell acute lymphoblastic leukemia and phenotype
Menée sur 3 107 cas et 6 211 témoins, cette étude d'association sur le génome entier identifie des variants situés sur les régions chromosomiques 10p12.2 et 10p14 en association avec un risque accru de leucémie lymphoblastique aiguë à précurseurs B chez les enfants
Acute lymphoblastic leukemia (ALL) is the major pediatric cancer diagnosed in economically developed countries with B-cell precursor (BCP) ALL accounting for approximately 70% of ALL. Recent genome-wide association studies (GWASs) have provided the first unambiguous evidence for common inherited susceptibility to BCP-ALL identifying susceptibility loci at 7p12.2, 9p21.3, 10q21.2 and 14q11.2. To identify additional BCP-ALL susceptibility loci, we conducted a GWAS and performed a meta-analysis with a published GWAS totaling 1,658 cases and 4,723 controls with validation in 1,449 cases and 1,488 controls. Combined analysis identified novel loci mapping to 10p12.2 (rs10828317, odds ratio [OR]=1.23; P=2.30x10-9) and 10p14 marked by rs3824662 (OR=1.31; P=8.62x10-12). rs10828317 is responsible for the N215S polymorphism in exon 7 of PIP4K2A and rs3824662 localizes to intron 3 of the transcription factor and putative tumor suppressor gene GATA3. The rs10828317 association was shown to be specifically associated with hyperdiploid ALL whereas the rs3824662 associated risk was confined to non-hyperdiploid non-TEL-AML1+ALL. The risk allele of rs3824662 was correlated with older age at diagnosis (P<0.001) and significantly worse event free survivorship (P<0.0001). These findings provides further insights into the genetic and biological basis of inherited genetic susceptibility to BCP-ALL and the influence of constitutional genotype on disease development.