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Context: Although cure rates of childhood acute lymphoblastic leukemia (ALL) have improved with risk-adapted therapy, stark racial disparities persist in both the incidence and treatment outcomes of ALL. There is a paucity of data describing the genetic basis of these disparities, especially in relation to modern ALL molecular taxonomy and in the context of contemporary treatment regimens. Objective: Determine the associations of genetic ancestry with ALL biology and the relevance of genetic ancestry to survival outcomes of modern ALL therapy. Design: This was a multi-national genomic study of 2,428 children with ALL in front-line trials from the United States, Singapore, Malaysia, and Guatemala, representing diverse populations of European, African, Native American, East Asian, and South Asian descent. We performed RNA sequencing to characterize ALL molecular subtype and genetic ancestry and then evaluated associations of genetic ancestries with ALL biology and treatment outcomes. Results: Of 21 ALL subtypes, 11 showed significant associations with ancestry. The frequency of somatic DUX4 gene rearrangement was positively correlated with both East Asian and South Asian ancestries, and alterations in ZNF384 and PAX5 increased with East Asian ancestry. By contrast, occurrence of CRLF2 rearrangements was linked to Native American ancestry. ETV6-RUNX1 fusion became less frequent as Native American ancestry increased, with the opposite observed for ETV6-RUNX1-like. There was a marked preponderance of T-ALL in children of African descent. African ancestry was also positively correlated with the prevalence of TCF3-PBX1 and MEF2D fusions. Survival outcomes differed significantly by genetic ancestry, where African and Native American ancestries were both associated with poorer event-free survival (African: HR, 2.3; 95% CI, 1.4–3.8; P=0.001; Native American: HR, 2.5; 95% CI, 1.0–5.9; P=0.044) and overall survival (African: HR, 2·4; 95% CI, 1.2-4.7; P=0.012 for African; Native American: HR, 3.3; 95% CI, 1.1-10.0; P=0.033). Importantly, even after adjusting for biological subtypes and clinical features, Native American and African ancestries remained independently associated with poor prognosis. Conclusions: ALL biology and prognosis are highly associated with genetic ancestry, pointing to a genetic basis for racial disparities in ALL. Biology-driven treatment individualization is needed to eliminate racial gaps in outcomes.

BACKGROUND Children of Hispanic ancestry have a higher incidence of acute lymphoblastic leukemia (ALL) compared with other ethnic groups, but to the authors' knowledge, the genetic basis for these racial disparities remain incompletely understood. Genome-wide association studies of childhood ALL to date have focused on inherited genetic effects; however, maternal genetic effects (the role of the maternal genotype on phenotype development in the offspring) also may play a role in ALL susceptibility. METHODS The authors conducted a family-based exome-wide association study of maternal genetic effects among Hispanics with childhood B-cell ALL using the Illumina Infinium HumanExome BeadChip. A discovery cohort of 312 Guatemalan and Hispanic American families and an independent replication cohort of 152 Hispanic American families were used. RESULTS Three maternal single-nucleotide polymorphisms (SNPs) approached the study threshold for significance after correction for multiple testing (P

Widely used as anticancer and immunosuppressive agents, thiopurines have narrow therapeutic indices owing to frequent toxicities, partly explained by TPMT genetic polymorphisms. Recent studies identified germline NUDT15 variation as another critical determinant of thiopurine intolerance, but the underlying molecular mechanisms and the clinical implications of this pharmacogenetic association remain unknown. In 270 children enrolled in clinical trials for acute lymphoblastic leukemia in Guatemala, Singapore and Japan, we identified four NUDT15 coding variants (p.Arg139Cys, p.Arg139His, p.Val18Ile and p.Val18_Val19insGlyVal) that resulted in 74.4-100% loss of nucleotide diphosphatase activity. Loss-of-function NUDT15 diplotypes were consistently associated with thiopurine intolerance across the three cohorts (P = 0.021, 2.1 × 10(-5) and 0.0054, respectively; meta-analysis P = 4.45 × 10(-8), allelic effect size = -11.5). Mechanistically, NUDT15 inactivated thiopurine metabolites and decreased thiopurine cytotoxicity in vitro, and patients with defective NUDT15 alleles showed excessive levels of thiopurine active metabolites and toxicity. Taken together, these results indicate that a comprehensive pharmacogenetic model integrating NUDT15 variants may inform personalized thiopurine therapy.

Children of Hispanic ancestry have a higher incidence of acute lymphoblastic leukemia (ALL) compared with other ethnic groups, but to the authors' knowledge, the genetic basis for these racial disparities remain incompletely understood. Genome-wide association studies of childhood ALL to date have focused on inherited genetic effects; however, maternal genetic effects (the role of the maternal genotype on phenotype development in the offspring) also may play a role in ALL susceptibility.The authors conducted a family-based exome-wide association study of maternal genetic effects among Hispanics with childhood B-cell ALL using the Illumina Infinium HumanExome BeadChip. A discovery cohort of 312 Guatemalan and Hispanic American families and an independent replication cohort of 152 Hispanic American families were used.Three maternal single-nucleotide polymorphisms (SNPs) approached the study threshold for significance after correction for multiple testing (P1.0 × 10In what to the authors' knowledge is the first family-based based exome-wide association study to investigate maternal genotype effects associated with childhood ALL, the results did not implicate a strong role of maternal genotype on disease risk among Hispanics; however, 3 maternal SNPs were identified that may play a modest role in susceptibility. Cancer 2016;122:3697-704. © 2016 American Cancer Society.