The Impact of Genetic Ancestry on the Biology and Prognosis of Childhood Acute Lymphoblastic Leukemia

INTRODUCTION Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Despite improvements in treatment over the past few decades, stark racial disparities persist in disease risk and cure rates. 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. To this end, we sought to determine the associations of genetic ancestry with ALL biology, and the relevance of genetic ancestry to survival outcomes of modern ALL therapy. METHODS This was a multi-national genomic study of 2,428 children with ALL on front-line trials from United States (St Jude Children's Research Hospital and Children's Oncology Group), South-East Asia (Ma-Spore trials) and Latin America (Guatemala), representing diverse populations of European (EUR), African (AFR), Native American (NA), East Asian (EAS), and South Asian (SAS) descent. We performed RNA-sequencing to characterize ALL molecular subtype, and also estimated their genetic ancestral composition by comparing allele frequencies of patient and reference genomes (1000 Genomes Project reference populations). For categorization of patients into racial groups, individuals were classified based on composition of genetic ancestry as: “white” (EUR >90%), “black” (AFR >70%), “Hispanic” (NA >10% and NA greater than AFR), “East Asian” (EAS >90%), “South Asian” (SAS >70%), with the rest defined as “Other”. We then evaluated the associations of ancestry with ALL molecular subtypes and survival. RESULTS Genetic ancestral composition of the entire cohort is shown in Figure 1A. Of 21 ALL subtypes, 11 showed significant associations with ancestry. Hyperdiploid ALL was most common in white children (30.6%) and the least frequent in blacks (14.4%) (P