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 novel high-risk subtype with a gene expression signature resembling Philadelphia chromosome-positive ALL and a 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 single susceptibility locus for Ph-like ALL (GATA3, rs3824662, P=2.17×10−14, odds ratio [OR]=3.85, for Ph-like ALL vs. non-ALL; P=1.05×10−8, OR=3.25, for Ph-like ALL vs. non-Ph-like ALL) that was independently validated. The rs3824662 risk allele was associated with somatic lesions underlying Ph-like ALL (i.e., CRLF2 rearrangement, JAK mutation, and IKZF1 deletion) and directly influenced GATA3 transcription. Finally, GATA3 SNP genotype was also associated with early treatment response and the risk of ALL relapse. Our results provide insights into interactions between host and tumor genomes and their importance in ALL pathogenesis and prognosis.

A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults

“…For the ALL cases in the COG P9906 trial, genome-wide SNP genotyping was performed by using Affymetrix Human SNP Array 500K, and GATA3 SNPs were genotyped by polymerase chain reaction and Sanger sequencing, as described previously. 36 We did not observe evidence of potential genotyping errors in the germline DNA because of tumor cell contamination (data not shown).…”

Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults

“…9 Genome-wide association studies in children and AYAs with ALL have identified inherited genetic variants in GATA3 that are associated with Ph-like ALL, and show an increased frequency in Hispanics and individuals with Native American or indigenous genetic ancestry. 33,34 Together, these data provide a plausible explanation for increased incidence and poor outcomes of Hispanic patients with B-ALL and may explain the higher incidence of Ph-like ALL seen in adults within the United States vs other non-Hispanic Northern European populations. 35,36 The significantly high number of patients of Hispanic ethnicity in our study reflects the referral pattern for our institution.…”

Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine

“…[86][87][88][89][90] Associations with specific ALL subtypes and relapse have also been identified. [91][92][93][94][95] Several genes such as IKZF1, CEBPE, and GATA3 encode transcription factors that are also targets of somatic genetic alteration in ALL.…”

“…In addition, ARID5B polymorphisms are associated with ALL risk and outcome in specific ethnic groups, 92 and GATA3 variants are associated with Ph-like ALL. 94 Deleterious germline mutations have been identified in familial and sporadic ALL. In addition to the germline TP53 and Ras mutations observed in LH ALL, 15 additional hypodiploid cases harbor germline mutations involving genes mediating DNA repair that are likely to be pathogenic.…”