Novel susceptibility variants at the ERGlocus for childhood acute lymphoblastic leukemia in Hispanics

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Characterized by high levels of Native American ancestry, Hispanics are disproportionally affected by this cancer with high incidence and inferior survival. However, the genetic basis for this disparity remains poorly understood because of a paucity of genome-wide investigation of ALL in Hispanics. Performing a genome-wide association study (GWAS) in 940 Hispanic children with ALL and 681 ancestry-matched non-ALL controls, we identified a novel susceptibility locus in the ERGgene (rs2836365; P= 3.76 × 10−8; odds ratio [OR] = 1.56), with independent validation (P= .01; OR = 1.43). Imputation analyses pointed to a single causal variant driving the association signal at this locus overlapping with putative regulatory DNA elements. The effect size of the ERGrisk variant rose with increasing Native American genetic ancestry. The ERGrisk genotype was underrepresented in ALL with the ETV6-RUNX1fusion (P< .0005) but enriched in the TCF3-PBX1subtype (P< .05). Interestingly, ALL cases with germline ERGrisk alleles were significantly less likely to have somatic ERGdeletion (P< .05). Our results provide novel insights into genetic predisposition to ALL and its contribution to racial disparity in this cancer.