Genes at the Crossroad of Primary Immunodeficiencies and Cancer

Abstract

Primary immunodeficiencies (PIDs) are a heterogeneous group of inherited disorders affecting one or multiple components of the innate and/or adaptive immune system. Currently, over 300 underlying genetic defects have been discovered. The most common clinical findings in patients with PIDs are infections, autoimmunity, and malignancies. Despite international efforts, the cancer risk associated with PIDs, given the heterogeneous character of this group of diseases, is difficult to estimate. The diverse underlying mechanisms of cancer in PID add another layer of complexity. Treatment of cancer within a context of PID is complicated by serious toxicities and long-term effects, including second malignancies. This review will focus on the little-known crossroad between PID and cancer genes and the value thereof for directing future research on our understanding of cancer in PID and for the identification of early cancer biomarkers in PID patients.

Genes Common in Primary Immunodeficiencies and Cancer Display Overrepresentation of Codon CTG and Dominant Role of Selection Pressure in Shaping Codon Usage

“…Primary immunodeficiency diseases (PIDs) encompass a heterogeneous group of heritable genetic disorders into which the immune system is partially or fully non-functional [1]. PIDs may culminate in increased susceptibility to infections, autoimmunity, inflammatory organ damage, and malignancy [2]. Initial evidence for linkages between cancer and primary immunodeficiencies (PIDs) was first reported in 1958 [3,4].…”

“…There is at least a 1.6-fold greater risk of malignancies in PID patients in comparison to the general population [6], and lymphomas [7] and skin tumors are the commonest ones [8]. Malignancy is considered as a diagnostic marker in a few PIDs [European Society of Immunodeficiencies (ESID) (https://esid.org (accessed on 26 June 2021))] and is the second leading cause of mortality in PID patients [2]. The information regarding the genetic basis of PIDs and malignancy predisposition is chiefly based on monogenic disorders.…”

Inborn Errors of Immunity and Cancer

“…Immunologists and oncologists should interact to monitor and promptly diagnose the potential development of cancer in known IEI patients, as well as an underlying IEI in patients with newly diagnosed cancers with suggestive medical history or high rate of therapy-related toxicity [ 139 ]. As many of both IEI and cancer predisposition genes are still unexplored, the intersection of the relevant lists may represent a significant opportunity for a potential genic and molecular targeted approach.…”

“…Finally, the efficacy of adoptive T cell therapies such as chimeric antigen receptor (CAR) T cells is still uncertain [ 139 ]. The role of these targeted therapies is still under discussion, as they could cause an increased risk for tumorigenesis as a result of immune manipulation in the context of an underlying immune deficiency or immune dysregulation [ 132 ].…”

Hereditary Predisposition to Hematopoietic Neoplasms

“…62 It is important to note that several monogenic DNA repair defects associated with cancer susceptibility have been classified as XCIND (X-ray susceptibility, cancer, immunodeficiency, and neurologic defects), which also includes the aforementioned syndromes such as ataxia telangiectasia and Nijmegen breakage syndrome. [131][132][133][134] CLONAL PLASMA CELL DISORDERS/ DYSPROTEINEMIAS Similar to lymphoid neoplasms, familial clusters of monoclonal gammopathy of undetermined significance, MM, and Waldenstrom macroglobulinemia have been noted in population studies. In 2018, KDM1A/ LSD1 was identified as the first inherited autosomal dominant gene, with an increased predisposition to develop MM.…”