Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse

Abstract

Recent genomic profiling of childhood acute lymphoblastic leukemia (ALL) identified a high-risk subtype with an expression signature resembling that of Philadelphia chromosome-positive ALL and poor prognosis (Ph-like ALL). However, the role of inherited genetic variation in Ph-like ALL pathogenesis remains unknown. In a genome-wide association study (GWAS) of 511 ALL cases and 6,661 non-ALL controls, we identified a susceptibility locus for Ph-like ALL (GATA3, rs3824662; P = 2.17 × 10(-14), odds ratio (OR) = 3.85 for Ph-like ALL versus non-ALL; P = 1.05 × 10(-8), OR = 3.25 for Ph-like ALL versus non-Ph-like ALL), with independent validation. The rs3824662 risk allele was associated with somatic lesions underlying Ph-like ALL (CRLF2 rearrangement, JAK gene mutation and IKZF1 deletion) and with variation in GATA3 expression. Finally, genotype at the GATA3 SNP was also associated with early treatment response and risk of ALL relapse. Our results provide insights into interactions between inherited and somatic variants and their role in ALL pathogenesis and prognosis.

Figure 1. Genome wide association study (GWAS) of the susceptibility of Ph-like ALL

The association between genotype and Ph-like ALL was evaluated using logistic regression model for 718,890 SNPs in 75 Ph-like ALL and 6,661 non-ALL controls. P-values (−log 10 P, y axis) were plotted against respective chromosomal position of each SNP (x axis). The blue horizontal line indicates the genome-wide significant threshold (P<5×10⁻⁸). Gene symbol was indicated for the GATA3 locus at 10p14.

Figure 2. rs3824662 as a cis-acting regulatory element of GATA3 transcription

GATA3 SNP rs3824662 risk allele (the A allele) was associated with higher GATA3 mRNA in 56 unrelated lymphoblastoid cell lines from HapMap population (YRI) (A), and was related to increased DNase hypersensitivity (higher transcription activity) in 67 unrelated HapMap cell lines (YRI). GATA3 expression and DNase hypersensitivity at this locus were obtained from previously published datasets^,. (B). Genotype-expression association and genotype-DNase hypersensitivity association was evaluated using a linear regression model, adjusting genetic ancestry as appropriate. AU, arbitrary unit. Boxes include data between the twenty-fifth and the seventy-fifth percentiles.

Figure 3. GATA3 SNP rs3824662 risk allele frequency and the constellation of multiple “Ph-like ALL related” genomic lesions (CRLF2 lesion, JAK mutation, and IKZF1 deletion)

Patients in COG AALL0232, COG P9906, and COG P9905 cohorts were grouped as triple positive, double positive, single positive and triple negative based on their status for somatic CRLF2 lesion, JAK mutation, and IKZF1 deletion. Risk (A) allele frequency at rs3824662 was highest in patients carrying all three lesions and lowest in patients carrying no lesions at these three genes, with a positive correlation between A allele frequency and the cumulative number of lesions in three cohorts (P=6.9×10⁻⁵, P=0.0005 and P=7.6×10⁻⁵, respectively), as determined by the ordinal regression test adjusting genetic ancestry.

Figure 4. Genotype at GATA3 SNP rs3824662 and ALL treatment response

The cumulative incidence of relapse was compared by genotype at rs3824662 in the COG P9906 (A) and COG P9905 (B), with P value estimated by hazard regression test including ancestry as covariate. Early treatment response measured by minimal residual disease (MRD) at the end of induction was also related to genotype at rs3824662 in both COG P9906 (C) and COG P9905 (D), with P value estimated by Spearman Rank test. For both relapse and MRD, the allele linked to Ph-like ALL was also associated with worse treatment response.