Introduction: Patients with inborn errors of immunity (IEI) have a higher risk of developing lymphoma than the general population. However, the prevalence of IEI-related gene germline variants and its effect on disease occurrence and progress in Chinese pediatric patients with lymphoma has not been fully studied. Understanding characteristics of IEI-related gene genetic variants and its associations with disease in these patients may help to the early intervention.

Aims: The purpose of this study was to analyze IEI-related gene germline variants and the associations with patient clinical outcomes in Chinese pediatric patients with lymphoma.

Methods: From Jan.2020 to May.2025, a total of 565 patients with lymphoma (416 male/149 female; median age=9, range:1-18) treated at Beijing GoBroad Boren Hospital and multiple clinical centers of the China Network for Childhood Lymphomas (CNCL) were included in this retrospective study. Whole exome sequencing (WES) was performed on blood samples from these patients. The IEI-related gene germline variants were analyzed, and statistical analysis was performed to investigate their associations with patient clinical outcomes.

Results: Among the 565 patients analyzed, 385 (68.1%) were found to harbor IEI-related gene germline predisposition variants, with a total of 122 genes identified. The higher percentage of IEI-related genes were MPEG1 (23.1%), TNFAIP3 (12.7%), NCF2 (10.9%), TRIM38 (8.8%), ATM (7.5%), FANCA (7.3%), and BRCA2 (6.5%). According to the 2024 update of the phenotypic classification by the International Union of Immunological Societies (IUIS) expert committee, among 122 IEI-related genes, the autoinflammatory disease-related genes had the highest incidence of mutation (23.71%), such as TNFAIP3 (12.7%), HAVCR2 (5.19%) and CARD14 (4.68%).

Compared with the normal population from the gnomAD database, the incidence of MPEG1 p.P316S (23.12% vs 9.16%, p < 0.05), ATM p.H1380Y (5.19% vs 1.44%, p < 0.05), BRCA2 p.K2729N (3.90% vs 0.91%, p < 0.05), IFIH1 p.K365E (3.90% vs 0.76%, p < 0.05), and UNC13D p.G863D (3.12% vs 0.45%, p < 0.05) variants in pediatric lymphoma were significantly higher. These results indicate that these variants are significantly enriched in Chinese pediatric patients with lymphoma.

Univariate Cox regression analysis of overall survival (OS) and event-free survival (EFS) showed that, patients harboring the TRIM38 p.R164X variant (n = 31, HR = 2.23, 95% CI: 1.09-4.52, p = 0.023) had significantly worse OS than those without this variant, although no significant difference was observed in EFS.

Conclusions: Our study revealed the prevalence of germline variants of IEI-related gene in Chinese pediatric patients with lymphoma. The presence ofTRIM38 p.R164X germline variant in pediatric lymphoma might be associated with poor outcomes. In addition, the high incidence of mutation in autoinflammatory disease-related genes indicates that prolonged exposure to an inflammatory microenvironment may increase the risk of lymphoma. These results may help clinicians assess risk and tailor treatments for their patients. (Caiyan·Zhang·and·Ying Liu contributed equally, QinlongZheng and Yonghong·Zhang contributed equally).

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2025
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