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Blood. 2019 Feb 14;133(7):724-729. doi: 10.1182/blood-2018-07-862946. Epub 2018 Dec 3.

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

Author information

1
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN.
2
Children's Hospital and.
3
Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
4
Department of Laboratory Medicine, Precision Medicine Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
5
Division of Internal Medicine, Graduate Medical Education, MountainView Hospital, University of Nevada, Reno, NV.
6
Department of Pathology, St Jude Children's Research Hospital, Memphis, TN.
7
Department of Pediatric Hematology/Oncology, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong, China.
8
Department of Biostatistics, College of Public Health and Health Professions and College of Medicine, University of Florida, Gainesville, FL.
9
Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH.
10
Department of Pathology and.
11
Department of Pediatrics, The Ohio State University, Columbus, OH.
12
Department of Pediatrics, NYU Langone Medical Center, New York, NY.
13
Maine Children's Cancer Program, Scarborough, ME.
14
Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California San Francisco, San Francisco, CA.
15
Department of Pediatric Hematology Oncology, University of Texas Southwestern Medical Center, Dallas, TX.
16
Cook Children's Medical Center, Fort Worth, TX.
17
Department of Pediatrics, Duke University, Durham, NC.
18
Johns Hopkins Medical Institute, Baltimore, MD.
19
Division of Hematopathology, Department of Laboratory Medicine, University of Washington, Seattle, WA.
20
Unidad Nacional de Oncología Pediátrica, Guatemala City, Guatemala.
21
Department of Oncology and.
22
Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, TN.
23
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
24
Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA.
25
Department of Pediatrics, Benioff Children's Hospital, San Francisco, CA; and.
26
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA.

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.

PMID:
30510082
PMCID:
PMC6376278
[Available on 2020-02-14]
DOI:
10.1182/blood-2018-07-862946

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