Abstract
Genome-wide association studies (GWAS) have advanced our understanding of susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL); however, much of the heritable risk remains unidentified. Here, we perform a GWAS and conduct a meta-analysis with two existing GWAS, totaling 2442 cases and 14,609 controls. We identify risk loci for BCP-ALL at 8q24.21 (rs28665337, P = 3.86 × 10−9, odds ratio (OR) = 1.34) and for ETV6-RUNX1 fusion-positive BCP-ALL at 2q22.3 (rs17481869, P = 3.20 × 10−8, OR = 2.14). Our findings provide further insights into genetic susceptibility to ALL and its biology.
Highlights
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer in western countries, of which B-cell precursor acute lymphoblastic leukemia (BCP-ALL) accounts for approximately 80% of cases[1]
Pooling data from the three genome-wide association studies (GWAS), we derived joint odds ratios (ORs), 95% confidence intervals (CIs), and associated per allele P-values under a fixed-effects model for each single-nucleotide polymorphisms (SNPs) with MAF > 0.01
In addition to previously reported loci we identified three risk loci for BCP-ALL at 8q24.21 and 5q21.3, and for ETV6-RUNX1-positive ALL at 2q22.3 (Fig. 2, Tables 1 and 2, Supplementary Table 3). rs17481869 was genotyped in United Kingdom (UK) GWAS II and German GWAS, while rs28665337 was imputed in all three data sets, imputation fidelity was confirmed through Sanger sequencing in a subset of samples (r2 = 0.98, Supplementary Table 4)
Summary
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer in western countries, of which B-cell precursor acute lymphoblastic leukemia (BCP-ALL) accounts for approximately 80% of cases[1]. The etiology of ALL is poorly understood and no specific environmental risk factor has so far been identified aside from indirect evidence for an infective origin[2,3]. Independent of concordance disease in monozygotic twins, which has an in utero origin evidence, albeit indirect, for inherited predisposition to ALL is provided by the elevated risk seen in siblings of ALL cases[4]. Previous genome-wide association studies (GWAS)[5,6,7,8,9] have suggested susceptibility to ALL is polygenic, identifying single-nucleotide polymorphisms (SNPs) in eight loci influencing ALL risk at 7p12.2 (IKZF1), 9p21.3 (CDKN2A), 10p12.2 (PIP4K2A), 10q26.13 (LHPP), 12q23.1 (ELK3), 10p14 (GATA3), 10q21.2 (ARID5B), and 14q11.2 (CEBPE). We report two previously unidentified risk loci, providing further insights into the genetic and biological basis of this disease
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