ArticleCancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology2026
Characterization of Genetic Etiologic Factors for Pediatric Acute Lymphoblastic Leukemia in Large Childhood Cancer Survivorship Cohorts.
Xiaoxi Meng, Cheng Chen, Na Qin, Heather L Mulder, John Easton, Michael N Edmonson, Michael Rusch, Jinghui Zhang, Jason R Myers, Logan G Spector and 13 more
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In one paragraphArticle in Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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23 authors.
Xiaoxi MengDepartment of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee.ORCID 0000-0001-7217-2037 Cheng ChenDepartment of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee.ORCID 0000-0003-1053-3217 Na QinDepartment of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.ORCID 0000-0001-6878-9464 Heather L MulderDepartment of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.ORCID 0000-0003-2024-9498 John EastonDepartment of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.ORCID 0000-0003-4503-6608 Michael N EdmonsonDepartment of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.ORCID 0000-0003-0339-700X Michael RuschDepartment of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.ORCID 0000-0002-5363-1848 Jinghui ZhangDepartment of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.ORCID 0000-0003-3350-9682 Jason R MyersCenter for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee.ORCID 0000-0002-0341-0860 Stephen J ChanockDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland.ORCID 0000-0002-2324-3393 Jun J YangDepartment of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.ORCID 0000-0002-0770-9659 Jian XuCenter of Excellence for Leukemia Studies, Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.ORCID 0000-0003-1988-7337 Charles G MullighanDepartment of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.ORCID 0000-0002-1871-1850 Melissa M HudsonDepartment of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee.ORCID 0000-0001-6984-2407 Kirsten K NessDepartment of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee.ORCID 0000-0002-2084-1507 Gregory T ArmstrongDepartment of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee.ORCID 0000-0001-8722-4207 Nilanjan ChatterjeeDepartment of Biostatistics, School of Medicine, Johns Hopkins University, Baltimore, Maryland.ORCID 0000-0002-9060-008X Zhaoming WangDepartment of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee.ORCID 0000-0001-7556-3869 Funding
Mach-LETSGO: Machine-LEarning of Treatment, Survey, and Genetics towards Obtaining Correct Classification of Chronic Conditions in Adult Survivors in the Childhood Cancer Survivor Study - CCSS SupplU24CA055727 · NCI · UNIVERSITY OF MINNESOTA TWIN CITIES · PI Gregory Armstrong · 1999 to 2026
$96.7MThe St. Jude Lifetime CohortU01CA195547 · NCI · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI HUDSON, MELISSA M, NESS, KIRSTEN KIMBERLIE · 2015 to 2024
$14.9MGenetic pleiotropy across pediatric cancers, and cancer-related outcomesR01CA283333 · NCI · UNIVERSITY OF MINNESOTA · PI Cindy Im · 2024 to 2026
$2.2MThe St. Jude Lifetime Cohort StudyU01CA301480 · NCI · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI MELISSA M HUDSON, Kirsten Kimberlie Ness · 2025 to 2026
$2.1MTargeting Metabolic Liabilities of Leukemia-Initiating Cells (R01CA230631)R01CA230631 · NCI · UT SOUTHWESTERN MEDICAL CENTER · PI XU, JIAN · 2019 to 2023
$1.8MNCI NIH HHS R01 CA230631NCI NIH HHS R01 CA283333NCI NIH HHS U01 CA195547NCI NIH HHS U01 CA301480NCI NIH HHS U24 CA055727
6 · The paper itselfAbstract
backgroundGermline genetic susceptibility to pediatric acute lymphoblastic leukemia (pALL) remains incompletely characterized across the allelic spectrum, including ultrarare, high-penetrance cancer-predisposing variants (CPV).
methodsWe 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.
resultsCompared 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).
conclusionsThis 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.
Indexed as
Cancer SurvivorsGenetic Predisposition to DiseasePrecursor Cell Lymphoblastic Leukemia-LymphomaAdolescentCase-Control StudiesChildChild, PreschoolCohort StudiesFemaleGenome-Wide Association StudyGerm-Line MutationHumansMalePolymorphism, Single Nucleotide
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PMID42089785
PMCPMC13251607
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