Inherited Risk for Childhood Leukemia

Childhood leukemia is the most common pediatric malignancy, diagnosed in nearly a third of pediatric cancer patients. Awareness and identification of the hereditary component of childhood leukemia continues to increase. Childhood leukemia, especially acute lymphoblastic leukemia (ALL), has been attributed to a dysregulated immune system with different patterns of infectious exposure at a young age. Candidate gene studies have revealed inconsistent associations with specific SNPs related to folate metabolism, xenobiotic metabolism, DNA repair, immunity, and B-cell development. More recently, genome-wide association studies (GWAS) have demonstrated stronger associations with SNPs in B-cell development genes and increased risk for childhood ALL. Identical twins have been described with childhood leukemia due to presumed placental transfer, but non-twin siblings with childhood leukemia also have been very rarely reported suggesting a genetic link to disease susceptibility. In this chapter, we review the known hereditary cancer syndromes associated with leukemia which can be divided into six categories: (1) DNA repair syndromes, (2) RASopathies, (3) bone marrow failure syndromes, (4) immunodeficiency syndromes, (5) germline predisposition to leukemia, and (6) congenital syndromes.