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

Maoxiang Qian, Heng Xu, Virginia Perez-Andreu, Kathryn G. Roberts, Hui Zhang, Wenjian Yang, Shouyue Zhang, Xujie Zhao, Colton Smith, Meenakshi Devidas, Julie M. Gastier-Foster, Elizabeth Raetz, Eric Larsen, Esteban G. Burchard, Naomi Winick, W. Paul Bowman, Paul L. Martin, Michael Borowitz, Brent Wood, Federico Antillon-Klussmann, Ching-Hon Pui, Charles G. Mullighan, William E. Evans, Stephen P. Hunger, Mary V. Relling, Mignon L. Loh and Jun J. Yang

Key points

  • GWAS in Hispanics identified ERG as a novel ALL risk locus, with effect sizes correlated with Native American ancestry.

  • The ERG risk genotype was under-represented in ALL with the ETV6-RUNX1 fusion or somatic ERG deletion, but enriched in the TCF3-PBX1 subtype.

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, but 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 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 = 0.01, 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 sharply with increasing Native American genetic ancestry. The ERG risk genotype was under-represented in ALL with the ETV6-RUNX1 fusion (P < 0.0005) but enriched in the TCF3-PBX1 subtype (P < 0.05). Interestingly, ALL cases with germline ERG risk alleles were significantly less likely to have somatic ERG deletion (P < 0.05). Our results provide novel insights to genetic predisposition to ALL and its contribution to racial disparity in this cancer.

  • Submitted July 10, 2018.
  • Accepted November 13, 2018.