Common Variable Immunodeficiency-Associated Cancers: The Role of Clinical Phenotypes, Immunological and Genetic Factors

Luzia Bruns; Victoria Panagiota; Sandra von Hardenberg; Gunnar Schmidt; Ignatius Ryan Adriawan; Eleni Sogka; Stefanie Hirsch; Gerrit Ahrenstorf; Torsten Witte; Reinhold Ernst Schmidt; Faranaz Atschekzei; Georgios Sogkas

doi:10.3389/fimmu.2022.742530

Common Variable Immunodeficiency-Associated Cancers: The Role of Clinical Phenotypes, Immunological and Genetic Factors

Front Immunol. 2022 Feb 17:13:742530. doi: 10.3389/fimmu.2022.742530. eCollection 2022.

Authors

Affiliations

¹ Department of Rheumatology and Immunology, Hannover Medical School, Hanover, Germany.
² Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
³ Department of Human Genetics, Hannover Medical School, Hanover, Germany.
⁴ Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.
⁵ Hannover Medical School, Cluster of Excellence RESIST (EXC 2155), Hanover, Germany.

Abstract

Objective: The aim of this study was to investigate the prevalence of cancer and associating clinical, immunological, and genetic factors in a German cohort of patients with common variable immunodeficiency (CVID).

Methods: In this retrospective monocenter cohort study, we estimated the standardized incidence ratio (SIR) for different forms of cancer diagnosed in CVID patients. Furthermore, we evaluated the likely association of infectious and non-infectious CVID-related phenotypes with the diagnosis of cancer by calculation of the odds ratio. The genetic background of CVID in patients with cancer was evaluated with sequential targeted next-generation sequencing (tNGS) and whole-exome sequencing (WES). Patients' family history and WES data were evaluated for genetic predisposition to cancer.

Results: A total of 27/219 patients (12.3%) were diagnosed with at least one type of cancer. Most common types of cancer were gastric cancer (SIR: 16.5), non-melanoma skin cancer (NMSC) (SIR: 12.7), and non-Hodgkin lymphoma (NHL) (SIR: 12.2). Immune dysregulation manifesting as arthritis, atrophic gastritis, or interstitial lung disease (ILD) was associated with the diagnosis of cancer. Furthermore, diagnosis of NMSC associated with the diagnosis of an alternative type of cancer. Studied immunological parameters did not display any significant difference between patients with cancer and those without. tNGS and/or WES yielded a definite or likely genetic diagnosis in 11.1% of CVID patients with cancer. Based on identified variants in cancer-associated genes, the types of diagnosed cancers, and family history data, 14.3% of studied patients may have a likely genetic susceptibility to cancer, falling under a known hereditary cancer syndrome.

Conclusions: Gastric cancer, NMSC, and NHL are the most frequent CVID-associated types of cancer. Manifestations of immune dysregulation, such as arthritis and ILD, were identified as risk factors of malignancy in CVID, whereas studied immunological parameters or the identification of a monogenic form of CVID appears to have a limited role in the evaluation of cancer risk in CVID.

Keywords: CTLA-4; CVID; NF-κB1 (NF-kappaB1); cancer; cancer immune surveillance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Arthritis*
Cohort Studies
Common Variable Immunodeficiency* / complications
Common Variable Immunodeficiency* / diagnosis
Common Variable Immunodeficiency* / genetics
Genetic Predisposition to Disease
Humans
Lung Diseases, Interstitial* / complications
Lymphoma, Non-Hodgkin* / complications
Phenotype
Retrospective Studies
Stomach Neoplasms* / epidemiology