Genetic Predisposition for Acute Lymphoblastic Leukemia

Multiple empirical studies show that childhood acute lymphoblastic leukemia (ALL) has at least some degree of heritability with at least 12 rare monogenic conditions and 14 single-nucleotide polymorphisms (SNPs) being convincingly linked to ALL predisposition. Observations from 11 pediatric pancancer studies illustrate that high-penetrance genetic predisposition is seemingly rare in patients with ALL compared to childhood acute myeloid leukemia, solid and central nervous system tumors. In this chapter, the rare genetic conditions are divided into overt syndromes with moderate to severe noncancer phenotypes (e.g., ataxia–telangiectasia), and covert syndromes with either minimal or no other clinical manifestations than cancer risk, some of which are wholly or primarily confined to ALL (e.g., ETV6 and PAX5). The genes linked to high-penetrance ALL risk tend to cluster in certain pathways and show evidence of having been under significant evolutionary selective pressure. SNPs associated with increased risk of ALL are described, including how they may guide our understanding of ALL pathogenesis.