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 J Winick, W. Paul Bowman, Paul L. Martin, Michael Borowitz, Brent Wood, Federico Antillon-KlussmannChing Hon Pui, Charles G. Mullighan, William E. Evans, Stephen P. Hunger, Mary V. Relling, Mignon L. Loh, Jun J. Yang

Research output: Contribution to journalArticle

7 Citations (Scopus)

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 5 3.76 3 102 8 ; odds ratio [OR] 5 1.56), with independent validation (P 5 .01; OR 5 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.

Original languageEnglish (US)
Pages (from-to)724-729
Number of pages6
JournalBlood
Volume133
Issue number7
DOIs
StatePublished - Feb 14 2019

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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Hispanic Americans
Genes
North American Indians
Fusion reactions
Odds Ratio
DNA
Neoplasms
Genome-Wide Association Study
Genetic Predisposition to Disease
Alleles
Genotype
Genome
Incidence

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Qian, M., Xu, H., Perez-Andreu, V., Roberts, K. G., Zhang, H., Yang, W., ... Yang, J. J. (2019). Novel susceptibility variants at the ERG locus for childhood acute lymphoblastic leukemia in Hispanics. Blood, 133(7), 724-729. https://doi.org/10.1182/blood-2018-07-862946

Novel susceptibility variants at the ERG locus for childhood acute lymphoblastic leukemia in Hispanics. / Qian, Maoxiang; Xu, Heng; Perez-Andreu, Virginia; Roberts, Kathryn G.; Zhang, Hui; Yang, Wenjian; Zhang, Shouyue; Zhao, Xujie; Smith, Colton; Devidas, Meenakshi; Gastier-Foster, Julie M.; Raetz, Elizabeth; Larsen, Eric; Burchard, Esteban G.; Winick, Naomi J; Paul Bowman, W.; Martin, Paul L.; Borowitz, Michael; Wood, Brent; Antillon-Klussmann, Federico; Pui, Ching Hon; Mullighan, Charles G.; Evans, William E.; Hunger, Stephen P.; Relling, Mary V.; Loh, Mignon L.; Yang, Jun J.

In: Blood, Vol. 133, No. 7, 14.02.2019, p. 724-729.

Research output: Contribution to journalArticle

Qian, M, Xu, H, Perez-Andreu, V, Roberts, KG, Zhang, H, Yang, W, Zhang, S, Zhao, X, Smith, C, Devidas, M, Gastier-Foster, JM, Raetz, E, Larsen, E, Burchard, EG, Winick, NJ, Paul Bowman, W, Martin, PL, Borowitz, M, Wood, B, Antillon-Klussmann, F, Pui, CH, Mullighan, CG, Evans, WE, Hunger, SP, Relling, MV, Loh, ML & Yang, JJ 2019, 'Novel susceptibility variants at the ERG locus for childhood acute lymphoblastic leukemia in Hispanics', Blood, vol. 133, no. 7, pp. 724-729. https://doi.org/10.1182/blood-2018-07-862946
Qian, Maoxiang ; Xu, Heng ; Perez-Andreu, Virginia ; Roberts, Kathryn G. ; Zhang, Hui ; Yang, Wenjian ; Zhang, Shouyue ; Zhao, Xujie ; Smith, Colton ; Devidas, Meenakshi ; Gastier-Foster, Julie M. ; Raetz, Elizabeth ; Larsen, Eric ; Burchard, Esteban G. ; Winick, Naomi J ; Paul Bowman, W. ; Martin, Paul L. ; Borowitz, Michael ; Wood, Brent ; Antillon-Klussmann, Federico ; Pui, Ching Hon ; Mullighan, Charles G. ; Evans, William E. ; Hunger, Stephen P. ; Relling, Mary V. ; Loh, Mignon L. ; Yang, Jun J. / Novel susceptibility variants at the ERG locus for childhood acute lymphoblastic leukemia in Hispanics. In: Blood. 2019 ; Vol. 133, No. 7. pp. 724-729.
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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 5 3.76 3 102 8 ; odds ratio [OR] 5 1.56), with independent validation (P 5 .01; OR 5 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.",
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T1 - Novel susceptibility variants at the ERG locus for childhood acute lymphoblastic leukemia in Hispanics

AU - Qian, Maoxiang

AU - Xu, Heng

AU - Perez-Andreu, Virginia

AU - Roberts, Kathryn G.

AU - Zhang, Hui

AU - Yang, Wenjian

AU - Zhang, Shouyue

AU - Zhao, Xujie

AU - Smith, Colton

AU - Devidas, Meenakshi

AU - Gastier-Foster, Julie M.

AU - Raetz, Elizabeth

AU - Larsen, Eric

AU - Burchard, Esteban G.

AU - Winick, Naomi J

AU - Paul Bowman, W.

AU - Martin, Paul L.

AU - Borowitz, Michael

AU - Wood, Brent

AU - Antillon-Klussmann, Federico

AU - Pui, Ching Hon

AU - Mullighan, Charles G.

AU - Evans, William E.

AU - Hunger, Stephen P.

AU - Relling, Mary V.

AU - Loh, Mignon L.

AU - Yang, Jun J.

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N2 - 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 5 3.76 3 102 8 ; odds ratio [OR] 5 1.56), with independent validation (P 5 .01; OR 5 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.

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