TY - JOUR
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
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.
N1 - Funding Information:
This work was partly supported by a St. Baldrick’s Foundation International Scholar award (H.Z.); a St. Baldrick’s Foundation Scholar award and a Robert J. Arceci award (C.G.M.); National Institutes of Health grants P50 GM115279 (National Institute of General Medical Sciences), CA156449, CA21765, CA36401, CA98543, CA114766, CA98413, CA140729, and CA176063 (all from the National Cancer Institute), GM92666 (National Institute of General Medical Sciences), and HHSN261200800001E (National Cancer Institute); the National Key Research and Development Program of China (2016YFC0905000 [2016YFC0905001, 2016YFC0905002]); the National Natural Science Foundation of China (81522028, 81728003, and 81673452); and the American Lebanese Syrian Associated Charities.
Publisher Copyright:
© 2019 by The American Society of Hematology.
PY - 2019/2/14
Y1 - 2019/2/14
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 1028; 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.
AB - 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 1028; 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.
UR - http://www.scopus.com/inward/record.url?scp=85061493959&partnerID=8YFLogxK
U2 - 10.1182/blood-2018-07-862946
DO - 10.1182/blood-2018-07-862946
M3 - Article
C2 - 30510082
AN - SCOPUS:85061493959
SN - 0006-4971
VL - 133
SP - 724
EP - 729
JO - Blood
JF - Blood
IS - 7
ER -