CVID-Associated Tumors: Czech Nationwide Study Focused on Epidemiology, Immunology, and Genetic Background in a Cohort of Patients With CVID

Abstract

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 tumorsMethods: 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.

Incidence of malignancy in patients with common variable immunodeficiency according to therapeutic delay: an Italian retrospective, monocentric cohort study

“…It is possible that we observed very selected cases, with serious manifestations, as we operated in a tertiary care Centre. However, this data agrees with findings by Kralickova et al, who identified ITP as a potential risk factor for cancer development in CVID patients [22]. In addition, the observation further suggests that the immune dysregulation underlying CVID may promote malignant occurrence [22].…”

The emerging role of KDM5A in human cancer

“…KDM5A is associated with many non-cancer diseases, such as congenital heart disease (CHD) [ 82 ] and bacterial, viral, or parasitic infection [ 79 , 83 , 84 ]. It also mediates renal failure in lipopolysaccharide-induced sepsis of mice [ 85 ].…”

Current Understanding and Recent Developments in Common Variable Immunodeficiency Associated Autoimmunity

“…Conversely, CVID patients with autoimmune cytopenias had a higher frequency of CVID-associated non-infectious complications, including granulomatous and lymphoproliferative disease, as well as organ-specific autoimmune disease, but interestingly, not systemic autoimmunity (26). In a recent study of a 295 patient CVID cohort in the Czech Republic, immune thrombocytopenic purpura (ITP) was identified as a risk factor for malignancy, with over a 3-fold increase compared to those without ITP (27). Splenomegaly was also more common in patients with autoimmune cytopenias and was found to share some immunophenotypic characteristics, but the pathophysiology of this link is still not clearly understood (28).…”