Abstract IA38: What causes the increased risk of acute lymphoblastic leukemia in Latinos?

Abstract

Abstract Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and, despite high cure rates, remains one of the leading causes of cancer-related mortality in children. Moreover, childhood ALL survivors are faced with severe long-term treatment-related morbidities, including increased risk of cardiovascular disease, secondary cancers, and pulmonary disease. Children of Latino ethnicity have the highest incidence of ALL in the United States. This increased risk likely has a genetic component, although the rising incidence of ALL in recent decades, which is increasing fastest in Latinos, points towards a role for environmental exposures. In this talk, I will discuss recent research from our group and others that has shed light on the potential etiologies of the increased ALL risk in Latinos. Genome-wide association studies (GWAS) of childhood ALL have pinpointed several risk loci at genes involved in B-cell development and hematopoiesis. In our earlier studies of ALL in the genetically admixed Latino population of California, we capitalized on their altered linkage disequilibrium patterns (compared to non-Latino whites) to identify putative causal variants, including a missense SNP in CDKN2A. More recently, we performed a large multiethnic GWAS of ALL including Latinos, non-Latino whites, and African-Americans, and identified new ALL risk loci at 8q24 and IKZF3. Fine-mapping at known loci also helped to confirm an independent risk locus at chromosome 10p12.31 and pinpointed a likely causal variant in an enhancer region for BMI1. Our group and others previously showed that the risk allele frequencies of several loci, including ARID5B, PIP4K2A, and GATA3, are higher in Latino populations and are associated with Native American ancestry. In two recent, independent GWAS of ALL in Latinos, a novel risk locus was identified at the erythroblast transformation-specific (ETS)-related gene (ERG) on chromosome 21, which was found to confer stronger leukemia risk in Latinos than in non-Latino whites. Moreover, within Latinos the effect of this risk locus increased with increasing Native American ancestry. We subsequently confirmed ERG as the first identified genetic risk locus for ALL in children with Down syndrome (DS-ALL), in which the effect size was again stronger in Latino than in non-Latino white children with DS. Our research group has also identified varied associations between Latinos and non-Latino whites for risk factors pertaining to immune stimulation (childhood contacts) and infection (cytomegalovirus). Future studies of ALL risk factors in Latinos, including even larger GWAS, polygenic risk score analysis, admixture mapping, as well as continued investigation of environmental risk factors, will be critical for our understanding the etiology of this disease and for identifying possible avenues to reduce the ethnic disparity in ALL incidence. Citation Format: Adam J. de Smith, Qianxi Feng, Kyle M. Walsh, Soyoung Jeon, Libby M. Morimoto, Andrew T. DeWan, Charleston Chiang, Catherine Metayer, Xiaomei Ma, Joseph L. Wiemels. What causes the increased risk of acute lymphoblastic leukemia in Latinos? [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr IA38.