Genome-Wide Association Study of Susceptibility Loci for T-Cell Acute Lymphoblastic Leukemia in Children

Abstract

Background Acute lymphoblastic leukemia (ALL) is the most common cancer in children and can arise in B or T lymphoid lineages. Although risk loci have been identified for B-ALL, the inherited basis of T-ALL is mostly unknown, with a particular paucity of genome-wide investigation of susceptibility variants in large patient cohorts. Methods We performed a genome-wide association study (GWAS) in 1191 children with T-ALL and 12 178 controls, with independent replication using 117 cases and 5518 controls. The associations were tested using an additive logistic regression model. Top risk variants were tested for effects on enhancer activity using luciferase assay. All statistical tests were two sided. Results A novel risk locus in the USP7 gene (rs74010351, odds ratio [OR] = 1.44, 95% confidence interval [CI] = 1.27 to 1.65, P = 4.51 × 10–8) reached genome-wide significance in the discovery cohort, with independent validation (OR = 1.51, 95% CI = 1.03 to 2.22, P = .04). The USP7 risk allele was overrepresented in individuals of African descent, thus contributing to the higher incidence of T-ALL in this race/ethnic group. Genetic changes in USP7 (germline variants or somatic mutations) were observed in 56.4% of T-ALL with TAL1 overexpression, statistically significantly higher than in any other subtypes. Functional analyses suggested this T-ALL risk allele is located in a putative cis-regulatory DNA element with negative effects on USP7 transcription. Finally, comprehensive comparison of 14 susceptibility loci in T- vs B-ALL pointed to distinctive etiology of these leukemias. Conclusions These findings indicate strong associations between inherited genetic variation and T-ALL susceptibility in children and shed new light on the molecular etiology of ALL, particularly commonalities and differences in the biology of the two major subtypes (B- vs T-ALL).

Pediatric acute lymphoblastic leukemia

“…[23][24][25] Several variants display ancestry and ALL subtype-specific associations, such as those of GATA3 with Hispanics and Ph-like B-ALL, ERG with African Americans and TCF3-PBX1 B-ALL, and USP7 with African Americans and T-ALL with TAL1 deregulation. [26][27][28] Finally, germline genomic analysis has identified additional susceptibility variants in sporadic hyperdiploid B-ALL (NBN, ETV6, FLT3, SH2B3, and CREBBP), Down syndrome-associated B-ALL (IKZF1, NBN, RTEL1), and T-ALL (Fanconi-BRCA pathway mutations). [29][30][31]…”

Effects of NT5C2 Germline Variants on 6‐Mecaptopurine Metabolism in Children With Acute Lymphoblastic Leukemia

“…26 We used a large reference panel of human haplotypes from the Haplotype Reference Consortium (HRC r1.1 2016) in Michigan Imputation Server with ShapeIT (version 2.r790) as the phasing tool for imputation, following procedures described previously. 41 Imputed variants were filtered based on imputation quality, allele frequency, call rate, and deviation from Hardy-Weinberg equilibrium. Specifically, variants with one of the following features were excluded: imputation quality metric r 2 < 0.3 (indicating inadequate accuracy of the imputed genotype); minor allele frequency in < 1% in either one of our two patient cohorts; Hardy-Weinberg equilibrium P value < 5.00 × 10 -4 ; variants located outside NT5C2 locus (beyond 100 kb of the first and last NT5C2 exons).…”

The Genome in a Three-Dimensional Context: Deciphering the Contribution of Noncoding Mutations at Enhancers to Blood Cancer

“…Risk loci frequently span noncoding regions ( 6 , 68 ) and, in fact, cluster at enhancers ( 1 ). The single-nucleotide polymorphisms (SNPs) or structural variants (SVs) can alter the binding of transcription factors or structural proteins to regulatory elements by modifying recognition motifs or modulating accessibility, thus altering the expression of their target genes ( Figure 2 ).…”