Characterization of Genetic Etiological Factors for Pediatric Acute Lymphoblastic Leukemia in Large Childhood Cancer Survivorship Cohorts

BACKGROUND: Germline genetic susceptibility to pediatric acute lymphoblastic leukemia (pALL) remains incompletely characterized across the allelic spectrum, including ultra-rare, high-penetrance cancer predisposing variants (CPVs). METHODS: We analyzed germline genetic data from 3,208 pALL survivors, 7,821 non-pALL survivors, and 377 non-cancer controls from the St. Jude Lifetime Cohort Study and the Childhood Cancer Survivor Study. We evaluated enrichment of ultra-rare CPVs in 60 curated cancer predisposition genes and conducted a genome-wide association study (GWAS) meta-analysis of common and low-frequency variants. RESULTS: Compared with non-cancer controls, pALL survivors showed significant enrichment of ultra-rare CPVs in BRCA1, PALB2, and PTPN11, in addition to established susceptibility genes CDKN2A and TP53. GWAS meta-analysis replicated 93% of previously reported pALL risk variants, with seven loci achieving genome-wide significance (P < 5 × 10⁻⁸). Two novel variants were identified: rs112425636 within SECTM1 (OR = 1.60, 95% CI = 1.39-1.84, P = 2.77 × 10⁻¹¹) and rs1821340 at 8q24.21 (OR = 1.33, 95% CI = 1.22-1.44, P = 1.63 × 10⁻¹¹). The rs112425636 risk allele was associated with reduced SECTM1 expression in B-cell pALL tumors. Median PRS was significantly higher in pALL survivors than in non-pALL survivors and non-cancer controls (P = 6.64 × 10⁻¹⁴⁷). SNP-based heritability was 0.19 (SE = 0.054). CONCLUSIONS: This study comprehensively characterizes the genetic etiology of pALL by integrating ultra-rare and common germline variation, expanding the spectrum of inherited risk factors. IMPACT: These findings advance understanding of pALL genetic architecture and inform future risk stratification.