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

Abstract

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 ERG gene (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 ERG risk variant rose with increasing Native American genetic ancestry. The ERG risk genotype was underrepresented in ALL with the ETV6-RUNX1 fusion (P < .0005) but enriched in the TCF3-PBX1 subtype (P < .05). Interestingly, ALL cases with germline ERG risk alleles were significantly less likely to have somatic ERG deletion (P < .05). Our results provide novel insights into genetic predisposition to ALL and its contribution to racial disparity in this cancer.

Heritable variation at the chromosome 21 gene ERG is associated with acute lymphoblastic leukemia risk in children with and without Down syndrome

“…We previously performed a large, multi-ethnic genome-wide association study (GWAS) of childhood ALL, including 3,263 cases of which ~60% were of Latino ethnicity [ 5 ]. While we identified two novel risk loci, we did not identify Latino-specific risk loci, unlike a recent report from Qian et al [ 6 ]. We have performed whole-genome imputation of our Latino dataset and combined it with GWAS data from two additional, non-overlapping Latino childhood ALL case-control datasets to identify novel and/or Latino-specific risk loci.…”

“…The effect of this locus on ALL risk was recently reported to increase with increasing global Native American (NA) ancestry [ 6 ]. Here we examined local ancestry at the ERG locus ( Supplementary Material , Supplementary Fig.…”

“…This gene is frequently somatically mutated in ALL, adding to a growing list of genes that both predispose to ALL and drive tumorigenesis following somatic mutations. Insufficient patient data were available to investigate the relationship between ERG SNPs and somatic alterations; however, during preparation of this manuscript, Qian et al reported that the ERG risk genotype was negatively correlated with somatic ERG deletions [ 6 ], supporting that the SNP may somewhat mimic effects of somatic loss of ERG .…”

Childhood cancer incidence among specific Asian and Pacific Islander populations in the United States

“…This finding is similar to a previous report, 28 which showed a higher incidence of leukemia in registry data from Oceania compared to registries in East Asia. Finally, we also observed a higher incidence rate of Hodgkin Hispanics 33,35 and East Asians. 36,37 The most extensive transethnic replication in childhood cancer has been done within ALL.…”

Yet another susceptibility variant for ALL: what’s next?

“…In this issue of Blood, Zhao et al explored the role of low doses of the histone deacetylase inhibitor (HDACi) chidamide in restoring immune tolerance in patients with immune thrombocytopenia (ITP). 1 For their investigation, the authors used both an animal model and a translational model with patient samples. Their work adds to the knowledge about the pathophysiology of ITP and explores a novel therapeutic avenue for patients with refractory disease who need alternative therapies.…”