Effects of germline GATA3 variants on ALL somatic genomics and prognosis in multi-ethnic populations

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Abstract Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and the leading cause of disease-related death among children in the US. Taking a genome-wide association study (GWAS) approach, we and others have identified 17 genomic loci associated with susceptibility to ALL in children. In particular, our group reported germline genetic variants in the GATA3 gene that strongly influence the risk of developing Ph-like ALL, a novel and high-risk subtype of this pediatric cancer (Nat Genet 45:1494). Additionally, and importantly, GATA3 variants are also related to poor response to ALL therapy, high relapse rate, and are over-represented in Hispanic children, who face inferior survival relative to non-Hispanic whites. The potential prognostic value of GATA3 distinguishes this gene from the majority of ALL susceptibility genes identified thus far and points to the possibility of incorporating germline genetic factors into ALL risk stratification to further individualize leukemia therapy. However, a number of knowledge gaps exist: 1) we have yet to comprehensively examine ALL risk variants in GATA3 beyond the index SNP in the original GWAS; 2) the association of GATA3 variants with different subtypes within Ph-like ALL is incompletely understood, and 3) there is no study to compare germline GATA3 variants, somatic genomic features, and clinical variables for their relative and independent prognostic impacts in the context of contemporary ALL treatment regimens. Therefore, we hypothesize that germline GATA3 variants are independent prognostic factors in pediatric ALL and can be used to further improve risk classification, particularly among Hispanics. Collaborating with the Children's Oncology Group (COG), we will first comprehensively examine GATA3 germline polymorphisms and test their association with ALL genomic abnormalities in two national ALL frontline trials (AALL0331 and AALL1131 trials, N=4,062). Focusing on these two large clinical trials, we will evaluate effects of GATA3 variants on early treatment response, ALL relapse, and event-free survival, in conjunction with somatic genomic factors and clinical presenting features. Lastly, we will explore the contribution of GATA3 variants to inferior ALL outcome in Hispanics, utilizing the national epidemiologic cohort for pediatric leukemia disparities research, namely the REDIAL consortium (N=1,000) by integrating clinical, genetic, and socioeconomic variables. Our long-term goal is to integrate germline genetic factors such as GATA3 variants into ALL risk stratification to improve outcome, which represents a significant shift from the current paradigm that relies entirely on somatic genomics and clinical features. Here, we comprehensively leverage the NIH's investment in national pediatric ALL trials and also state-of-the-art genomic datasets related to ALL, thus making this project feasible within this time frame and also cost-effective.