Childhood malignancies in inborn errors of immunity: a multicenter cohort study.
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UNLABELLED: Inborn errors of immunity (IEI) increase susceptibility to malignancy, but pediatric multicenter data integrating immune phenotype, molecular findings, treatment, and outcome remain limited. We characterized malignancy patterns and outcomes in children with documented IEI in Türkiye. This retrospective multicenter cohort study included children younger than 18 years with a documented IEI diagnosis and malignancy, irrespective of diagnostic order, across 20 centers from 2000 to 2025. Clinical, molecular, treatment, and outcome data were summarized. Overall survival (OS) was estimated using the Kaplan-Meier method. Across the 20 participating centers, 1,309 children with documented IEI constituted the aggregate center-level reference population; the final analytic cohort included 85 children with documented IEI and malignancy, corresponding to a descriptive center-level frequency of 6.5%. Combined immunodeficiencies with associated or syndromic features were the largest category (49.4%), and ATM was the most frequently reported gene (35.3%). Non-Hodgkin lymphoma was most common (44.7%), followed by Hodgkin lymphoma (23.5%) and acute lymphoblastic leukemia (14.1%). IEI was diagnosed before malignancy in 58 patients (68.2%) and concurrently with or after malignancy in 27 (31.8%). Hematopoietic stem cell transplantation was performed in 17 patients (20.0%). At last documented contact, 38 patients (44.7%) had died; estimated 5-year OS was 70.5% (95% CI, 60.1-82.7), with no statistically significant difference across malignancy categories (log-rank P = 0.73). CONCLUSION: Childhood malignancy in this referral-based IEI cohort was predominantly lymphoid and occurred across distinct immune and molecular backgrounds. Integrating immune phenotype and molecular context may help guide multidisciplinary cancer assessment and management. WHAT IS KNOWN: • Inborn errors of immunity predispose children to malignancy, especially lymphoma. • Pediatric multicenter data integrating immune phenotype, molecular findings, treatment, and outcomes remain limited. WHAT IS NEW: • In this 20-center cohort integrating patient-level immunologic, treatment, and outcome data, IEI was diagnosed concurrently with or after malignancy in 27 of 85 children (31.8%). • All 11 mismatch-repair cases had central nervous system tumors or non-Hodgkin lymphoma; all 9 cases in the Epstein-Barr virus-control/immune-dysregulation group had lymphoma. Estimated 5-year OS was 70.5%.