Leukemia is the most common type of cancer in children. While historically considered mostly sporadic, childhood leukemia is now understood to be strongly associated with genetic risk factors, which may act through variable complex mechanisms including Mendelian inheritance, common variation, epigenetic phenomena and even cytogenetic syndromes and other congenital disorders.   

An increasing number of Mendelian conditions are now recognized for their association with childhood leukemia, where a single pathogenic variant significantly increases the disease risk. Examples include pathogenic variants in ETV6, IKZF1 and PAX5 implicated in B-lymphoblastic leukemia (B-ALL), TP53 in hypodiploid B-ALL, RUNX1 in familial platelet disorder with predisposition to acute myeloid leukemia (AML), and GATA2 in familial myelodysplastic syndrome and AML. Additionally, the significant contribution of common genetic variation to the risk of developing leukemia has been revealed through genome-wide association studies (GWAS). While the individual effect of common risk variants in genes like ARID5B, CEBPE, GATA3 and IKZF1 is usually modest, collectively they explain a large proportion of familial relative risk. Additionally, variants enriched in certain ancestral groups are being identified as major contributors to disparities in incidence and outcome in childhood leukemia. Hispanic/Latino (H/L) children have the highest risk of B-ALL in the US compared to other ancestral groups, and have a significantly worse outcome even after correcting for socioeconomic factors. Predisposing variants enriched in H/L populations in GATA3 and IKZF1 have been found to provide a biological basis for this health disparity for H/L children.

In addition to isolated leukemia predisposition, many well-known genetic syndromes are associated with an increased risk of childhood leukemia as part of a more complex phenotype. Individuals with Trisomy 21 (Down) syndrome have increased incidence of both AML and ALL, and diseases like Fanconi anemia and Bloom syndrome predispose individuals to leukemia due to defects in DNA repair mechanisms.

Timely identification of individuals with strong germline predisposition to hematologic malignancies is critical, as it allows clinical surveillance, early detection, and tailored treatment strategies including referral for allogeneic stem cell transplantation and familial testing. This mandates increased awareness among genetic professionals about growing number of genes, variants and genetic syndromes associated with leukemia risk.

In this session, speakers will provide an update on genetic and epigenetic factors implicated in pathogenesis of childhood leukemia, and describe the complex array of mechanisms through which such factors contribute to disease risk. Advanced understanding of genetic predisposition will be highlighted as a crucial component for risk assessment, early detection, and personalized treatment strategies in childhood leukemia.