Role of common host genome variants in Childhood Acute Lymphoblastic Leukemia

Childhood acute lymphoblastic leukemia (ALL) is a genetically heterogeneous disease, and while somatic alterations inform diagnosis and treatment stratification, germline variants - particularly common host genome variants - rarely influence clinical care. Over the past decade, various host genome variant studies have uncovered numerous common variants associated with ALL susceptibility, treatment efficacy, and toxicity risk. Yet, less than a handful have reached clinical implementation, with TPMT and NUDT15 variants being the only ones widely used clinically. Whether a variant can be readily translated into the clinical setting primarily depends on four features: (1) Phenotype severity, (2) phenotype rarity and the proportion of cases (overall or in subsets of patients) accounted for by genetic variants, (3) the application of the variant as an add-on clinical decision support tool, and (4) the availability, cost, and potential side effects of interventions and/or prophylaxis. Key barriers for such clinical translation include insufficient effect sizes, lack of replication across diverse populations, and lack of well-established treatment modification strategies. However, large-scale international collaborations can generate the necessary statistical power, including enabling more complex bioinformatic approaches, such as polygenic risk scores and more advanced machine learning strategies. In this review, we outline the necessary steps toward bridging the gap between genetic discovery and clinical practice.