Germline genomic variants associated with childhood acute lymphoblastic leukemia

Abstract

We identified germline single nucleotide polymorphisms (SNPs) associated with childhood acute lymphoblastic leukemia (ALL) and its subtypes. Using the Affymetrix 500K Mapping array and publicly available genotypes, we identified 18 SNPs whose allele frequency differed (P<1×10 −5 ) between a pediatric ALL population (n=317) and non-ALL controls (n=17,958). Six of these SNPs differed (P≤0.05) in allele frequency among four ALL subtypes. Two SNPs in ARID5B not only differed between ALL and non-ALL groups (rs10821936, P=1.4×10 −15 , odds ratio[OR]=1.91; rs10994982, P=5.7×10 −9 , OR=1.62) but also distinguished B-hyperdiploid ALL from other subtypes (rs10821936, P=1.62 ×10 −5 , OR=2.17; rs10994982, P=0.003, OR 1.72). These ARID5B SNPs also distinguished B-hyperdiploid ALL from other subtypes in an independent validation cohort (n=124 children with ALL) (P=0.003 and P=0.0008, OR 2.45 and 2.86, respectively) and were associated with methotrexate accumulation and gene expression pattern in leukemic lymphoblasts. We conclude that germline genomic variations affect susceptibility to and characteristics of specific ALL subtypes.Pediatric acute lymphoblastic leukemia (ALL) comprises biologically and clinically diverse subtypes. Somatically acquired genetic aberrations in ALL lymphoblasts are prognostic and can guide risk-directed therapy. 1 However, the extent to which germline variation contributes to susceptibility to ALL, to the acquisition of genetic aberrations that define ALL subtypes, and perhaps to the response to drug therapy among subtypes, is unknown. Candidate gene approaches have identified inherited polymorphisms in loci that may contribute to susceptibility to ALL, including the multidrug resistance gene ABCB1/MDR1, methylenetetrahydrofolate reductase (MTHFR), the glutathione-S-transferases as well as cellcycle inhibitor and DNA mismatch repair genes. 2-7 Lacking, however, are genome-wide studies that assess how inherited variation contributes to the development of ALL. Therefore, we conducted a genome-wide association study to identify germline single nucleotide polymorphisms (SNPs) in children with newly diagnosed ALL that may be associated with the development of ALL and with specific ALL subtypes.We first identified SNPs whose allele frequency differed between a discovery cohort of 317 children of European descent with ALL and 17,958 individuals of European descent without ALL from three independent control groups ( Supplementary Fig. 1). After applying quality control criteria, we evaluated 307,944 germline SNPs. Eighteen SNPs differed in allele frequency (using P-value thresholds specified in Supplementary Fig. 1) between patients with ALL and non-ALL controls ( We next compared the allele frequency of these 18 SNPs among four major ALL subtypes (Bother, B-hyperdiploid, t(12;21)/ETV6-RUNX1, and T-cell ALL) in the discovery cohort and found that six SNPs distinguished among the subtypes (P≤0.05) ( Table 2). The two ARID5B SNPs (rs10821936 and rs10994982) distinguished B-hyperdiploid ALL from all ...

Common genetic variation contributes significantly to the risk of childhood B-cell precursor acute lymphoblastic leukemia

“…Thus far, GWAS of ALL, including the parent study on which this current analysis is based, have identified four independent loci shown conclusively to be associated with ALL, and more specifically BCP-ALL risk-7p12.2 (IKZF1), 9p12 (CDKN2A/CDKN2B), 10q21.2 (ARID5B) and 14q11.2 (CEBPE). [4][5][6] While the risk of ALL associated with these common variants is not insignificant (RRs of 1.5-1.6), collectively they only underscore B8% of the genetic variance in BCP-ALL risk.…”

“…[4][5][6] These studies have robustly shown that singlenucleotide polymorphisms (SNPs) annotating the IKZF1 (7p12.2), CDKN2A (9p21.3), ARID5B (10q21.2) and CEBPE (14q11.2) genes influence disease risk (that is, P-values for associations o5.0 Â 10 À 8 ). [4][5][6] While each SNP only has a modest effect on an individual developing ALL, relative risks are among the strongest cancer associations identified by GWAS. 7 This is compatible with a scenario in which the inherited susceptibility to this malignancy has a strong polygenic basis.…”

Genomic profiling of high-risk acute lymphoblastic leukemia

“…26 A role for IKAROS in the pathogenesis of ALL is also supported by recent data from genome-wide association studies in which an inherited single-nucleotide polymorphism allele at the IKZF1 locus was associated with the risk of childhood ALL, a finding that has been identified in multiple studies and patient cohorts. [46][47][48] The mechanistic basis of this finding remains unclear, although it is notable that IKZF1 genotype was associated with the level of gene expression, 46 and the genes at the two other loci found to be associated with ALL risk in these studies, ARID5B and CEBPE, also encode transcriptional regulators and genes involved in lymphoid maturation, 49,50 suggesting that germline variation at these loci directly influences the risk of ALL.…”

HLA complex-linked heat shock protein genes and childhood acute lymphoblastic leukemia susceptibility

“…The role of inherited alleles in ALL development is less well established. Two genome-wide association studies have been performed in childhood ALL with similar results on the risk modification by previously unsuspected loci involved in transcriptional regulation and differentiation of B cell progenitors (Papaemmanuil et al 2009;Treviño et al 2009). …”