Genomics of childhood acute lymphoblastic leukemia in the Childhood Cancer and Leukemia International Consortium

PROJECT SUMMARY/ABSTRACT Globally, acute lymphoblastic leukemia (ALL) is the most common cancer in children 0-14 years of age, with an estimated 74,000 incident cases each year. Nearly 1,500,000 years of life are lost due to the disease annually; and because of their large, young populations, the burden of ALL is centered within south, southeast, and east Asia; the middle east and north Africa; and sub-Saharan Africa. These trends highlight the need for research addressing risk for ALL in global populations where the need is greatest. Incidence of ALL also shows distinct patterns by ancestry. In the United States, risk is highest in Latinos, followed by European and Asian/Pacific Islander children, while African-American children have by far the lowest rates. There is reason to believe these patterns may be based at least partially on genetics. For instance, incidence of childhood ALL among diaspora populations in the United States largely recapitulates international patterns of incidence. The germline genetic architecture of ALL risk revealed to date suggests that ALL has a stronger risk component accounted for by common polymorphic variants than is found in adult cancers, with genomewide association studies (GWAS) having identified over 15 common variants associated with B-cell precursor ALL (B-ALL, comprising ~85% of ALL cases), which together describe nearly a 10-fold difference in risk between the lowest and highest ends of distribution of polygenic risk score. However, these studies have largely examined European genomes. The Childhood Cancer and Leukemia International Consortium (CLIC) is ideally suited to understanding the genomic architecture of ALL risk in children of many ancestries. CLIC’s collective genomic datasets comprise ~12,000 children with ALL from five continents, making them both the largest and most diverse such datasets worldwide. Moreover, most of CLIC’s genomic data is embedded within epidemiologic studies, unlike the purely clinical studies to date. With this resource, which more than doubles the sample size over previous GWAS, we propose to: 1) estimate heritability of ALL using SNP-based methods in diverse populations including Africans/African- Americans (AFR), admixed Americans (i.e. Latinos; AMR), East Asians (EAS), Europeans (EUR), Middle Eastern/North Africans (MENA), South Asians (SAS), and Southeast Asians (SEA); 2) conduct comprehensive genomewide and local discovery for variants associated with ALL; and 3) create population-specific polygenic risk scores and examine their relationship to harmonized epidemiologic data within CLIC. At the conclusion of this study, CLIC will have articulated a far more comprehensive genetic epidemiology of ALL than exists today in populations that represent most of the children on earth; and, for the first time, will simultaneously consider non-genetic risk factors. We further will have prioritized candidate variants for functional validation and built a robust infrastructure for future analyses of CLIC’s genomic datasets.