Characterization of Genetic Etiologic Factors for Pediatric Acute Lymphoblastic Leukemia in Large Childhood Cancer Survivorship Cohorts.
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BACKGROUND: Germline genetic susceptibility to pediatric acute lymphoblastic leukemia (pALL) remains incompletely characterized across the allelic spectrum, including ultrarare, high-penetrance cancer-predisposing variants (CPV). METHODS: We analyzed germline genetic data from 3,208 pALL survivors, 7,821 non-pALL survivors, and 377 noncancer controls from the St. Jude Lifetime Cohort Study and the Childhood Cancer Survivor Study. We evaluated enrichment of ultrarare 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 noncancer controls, pALL survivors showed significant enrichment of ultrarare 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 7 loci achieving genome-wide significance (P < 5 × 10-8). Two novel variants were identified: rs112425636 within secreted and transmembrane protein 1 [SECTM1; odds ratio (OR) = 1.60; 95% confidence interval (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. The median polygenic risk score was significantly higher in pALL survivors than in non-pALL survivors and noncancer controls (P = 6.64 × 10-147). Single-nucleotide polymorphism-based heritability was 0.19 (standard error = 0.054). CONCLUSIONS: This study comprehensively characterizes the genetic etiology of pALL by integrating ultrarare and common germline variations, expanding the spectrum of inherited risk factors. IMPACT: These findings advance the understanding of pALL genetic architecture and inform future risk stratification.