Recent genomic profiling of acute lymphoblastic leukemia (ALL) has identified a novel high-risk subtype with a gene expression signature similar to that of BCR-ABL1-positive (Ph+) ALL and a poor prognosis. This novel BCR-ABL1-like ALL subtype is characterized by genomic aberrations targeting lymphoid development, cytokine receptor, and tyrosine kinase signaling pathways, e.g., IKZF1 deletion, CRLF2 rearrangements, and JAK mutations. However, the role of the inherited genetic variation in the pathogenesis of BCR-ABL1-like ALL remains unknown.Taking a genome-wide association study (GWAS) approach, we sought to examine germline single-nucleotide polymorphisms (SNPs) for their association with the predisposition to BCR-ABL1-like ALL. In the discovery GWAS, we compared germline SNP genotype frequencies between ALL cases with (N=75) vs. without (N=436) the BCR-ABL1-like expression signature enrolled on the high risk Children's Oncology Group (COG) AALL0232 protocol, and between BCR-ABL1-like ALL (N=75) vs. non-ALL controls (N=6,661). BCR-ABL1-like ALL was identified by prediction analysis of microarrays. After adjusting for genetic ancestry, we observed a single susceptibility locus on 10p14 signified by two SNPs within the GATA3 gene with genome-wide significant association (P=1.05×10-8 and P=2.62×10-7 [BCR-ABL1-like ALL vs. non-BCR-ABL1-like ALL]; P=2.17×10-14 and P=4.94×10-12 [BCR-ABL1-like ALL vs. non-ALL controls]). In a replication cohort of high-risk ALL, namely COG P9906, the disease risk alleles at both GATA3 polymorphisms were consistently over-represented in BCR-ABL1-like ALL (N=32) compared with 139 non-BCR-ABL1-like ALL (P=0.01 and P=0.004, respectively) and compared with an independent set of 5,755 non-ALL controls (P=3.69×10-5 and P=0.0001, respectively). This GATA3 SNP was also associated with GATA3 expression in lymphoblastoid cell lines (N=56, P=0.034) and in primary ALL blasts (COG AALL0232, N=511, P=9.2×10-8; COG P9906, N=173, P=3.6×10-6), indicating that this variant may function as a cis-acting element regulating GATA3 transcription. Ectopic overexpression of GATA3 in ALL cell lines led to global changes in gene expression, with a particular enrichment of genes within the BCR-ABL1-like ALL expression signature.In the discovery cohort (COG AALL0232), the GATA3 SNP was also significantly associated with CRLF2 rearrangements (P=9.64×10-7), JAK mutations (P=2.06×10-5), and IKZF1 deletion (P=0.0002), which was validated in COG P9906 (P=0.08, 0.008, and 0.002, respectively) and in a third independent cohort, COG P9905 (P=0.009, 0.05, and 0.0002, respectively). The GATA3 risk allele was further enriched among patients with multiple “BCR-ABL1-like ALL-related” lesions concurrently, with the highest frequency observed in cases with three genomic lesions, followed by those with one or two lesions, and lowest among patients without any of the three lesions (COG AALL0232, P=6.09×10-5; COG P9906, P=0.0005; and COG P9905, P=7.6×10-5). Interestingly, the association of the GATA3 SNP with BCR-ABL1-likeness remained significant after adjusting for all three genomic lesions (P=0.001).We further examined the relationships between GATA3 SNP genotype and ALL relapse. In the COG P9906 cohort, the GATA3 allele linked to BCR-ABL1-like ALL was associated with a higher risk of relapse (N=222, P=0.002) and poor early treatment response as measured by minimal residual disease (N=193, P=9.8×10-5), which was validated in COG P9905 (N=777, P=0.007 and N=710, P=0.039, respectively). Of interest, the GATA3 allele associated with relapse and BCR-ABL1-like ALL was more frequent in Hispanics (40%) than in populations of European descent (12%), consistent with the inferior treatment outcome for Hispanic children with ALL.In conclusion, we have identified common GATA3 germline variants associated with BCR-ABL1-like ALL, somatic molecular lesions characteristic of this subtype, and importantly the risk of ALL relapse. These results suggest plausible interactions between host and tumor genomic variations in ALL pathogenesis and drug response. Disclosures:Evans:St. Jude: In accordance with institutional policy, St. Jude allocates a portion of the income it receives from licensing inventions and tangible research materials to those researchers responsible for creating this intellectual property. Patents & Royalties, Under this policy, I and/or my spouse have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics., Under this policy, I and/or my spouse have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics. Other. Relling:St. Jude: In accordance with institutional policy, St. Jude allocates a portion of the income it receives from licensing inventions and tangible research materials to those researchers responsible for creating this intellectual property. Patents & Royalties, Under this policy, I and/or my spouse have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics., Under this policy, I and/or my spouse have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics. Other.
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