Background: Common variable immunodeficiency disorder (CVID) is one of the most frequent inborn errors of immunity, increased occurrence of malignancies, particularly lymphomas, and gastric cancers, has long been noted among CVID patients. Multifactorial etiology, including immune dysregulation, infections, chronic inflammation, or genetic background, is suggested to contribute to tumor development. Here, we present the results of the first Czech nationwide study focused on epidemiology, immunology and genetic background in a cohort of CVID patients who also developed tumors Methods: The cohort consisted of 295 CVID patients followed for 3,070 patient/years. Standardized incidence ratio (SIR) was calculated to determine the risk of cancer, and Risk ratio (RR) was established to evaluate the significance of comorbidities. Moreover, immunophenotyping, including immunoglobulin levels and lymphocyte populations, was assessed. Finally, Whole exome sequencing (WES) was performed in all patients with lymphoma to investigate the genetic background. Results: Twenty-five malignancies were diagnosed in 22 patients in a cohort of 295 CVID patients. SIR was more than 6 times greater in comparison to the general population. The most common neoplasias were gastric cancers and lymphomas. History of Immune thrombocytopenic purpura (ITP) was established as a potential risk factor, with over 3 times higher risk of cancer development. The B cell count at diagnosis of lymphoma was reduced in the lymphoma group; moreover, post-treatment B and T cell lymphopenia, associated with poorer outcome, was found in a majority of the patients. Intriguingly, no NK cell depression was observed after the chemotherapy. WES revealed heterogeneous genetic background among CVID patients with tumors, identifying gene variants associated with primary immunodeficiencies (such as CTLA4, PIK3CD, PMS2) and/or increased cancer susceptibility (including BRCA1, RABEP1, EP300, KDM5A). Conclusions: The incidence of malignancy in our CVID cohort was found to be more than 6 times greater compared to the general population. Gastric cancers and lymphomas were the most frequently diagnosed tumors. ITP was identified as a risk factor for malignancy in CVID patients. WES analysis confirmed a wide genetic heterogeneity among CVID patients. The identified causative or modifying gene variants pointed to errors in mechanisms contributing to both immunodeficiency and malignancy.

Childhood Leukemia Investigation Prague 2nd Faculty of Medicine Charles University Prague Czechia

Department of Allergology and Clinical Immunology Faculty of Medicine Charles University and University Hospital in Hradec Kralove Hradec Kralove Czechia

Department of Allergology and Clinical Immunology Faculty of Medicine in Pilsen Charles University and University Hospital Pilsen Pilsen Czechia

Department of Allergology and Clinical Immunology Institute of Health Usti nad Labem Czechia

Department of Allergology nad Clinical Immunology Faculty of Medicine Masaryk University and St Anne's University Hospital in Brno Brno Czechia

Department of Clinical Immunology and Allergology Institute for Clinical and Experimental Medicine Prague Czechia

Department of Immunology 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czechia

Department of Informatics and Quantitative Methods Faculty of Informatics and Management University of Hradec Kralove Hradec Kralove Czechia

Department of Pneumology Regional Thomas Bata Hospital Zlin Czechia

Institute of Immunology and Microbiology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czechia

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