Current Understanding and Future Research Priorities in Malignancy Associated With Inborn Errors of Immunity and DNA Repair Disorders: The Perspective of an Interdisciplinary Working Group

Abstract

Patients with inborn errors of immunity or DNA repair defects are at significant risk of developing malignancy and this complication of their underlying condition represents a substantial cause of morbidity and mortality. Whilst this risk is increasingly well-recognized, our understanding of the causative mechanisms remains incomplete. Diagnosing cancer is challenging in the presence of underlying co-morbidities and frequently other inflammatory and lymphoproliferative processes. We lack a structured approach to management despite recognizing the competing challenges of poor response to therapy and increased risk of toxicity. Finally, clinicians need guidance on how to screen for malignancy in many of these predisposing immunodeficiencies. In order to begin to address these challenges, we brought together representatives of European Immunology and Pediatric Haemato-Oncology to define the current state of our knowledge and identify priorities for clinical and research development. We propose key developmental priorities which our two communities will need to work together to address, collaborating with colleagues around the world.

Update on DNA-Double Strand Break Repair Defects in Combined Primary Immunodeficiency

“…The introduction of newborn screening for SCID will detect a number of these diseases, meaning that an accurate and speedy genetic diagnosis is imperative in order to define the most appropriate treatment regimen. Furthermore, the high incidence of lymphoid malignancies in these diseases should alert clinicians treating oncology patients to the possibility of an underlying systemic DNA repair disorder indicative of primary immunodeficiency [ 100 ], prior to embarking on treatment, to minimize treatment-related toxicities.…”

Hematopoietic Stem Cell Transplantation for Combined Immunodeficiencies, on Behalf of IEWP-EBMT

“…It can lead to skin or visceral granulomatous lesions driven in some circumstances by persistent chronic infections such as vaccine-derived rubella virus (3). Increased susceptibility to malignancies, particularly lymphoma is observed (4). This can be due to impaired immunosurveillance to viral or tumoral antigens; chronic inflammation and infection with oncogenic viruses such as Epstein Barr Virus (EBV) can also promote lymphoproliferation.…”

HSCT provides effective treatment for lymphoproliferative disorders in children with primary immunodeficiency

“…During food challenges, we found that lipid-rich mammalian meats were associated with more consistent, severe reactions. 2 Thus, we hypothesized that glycolipid could activate allergic effector cells in alpha-gal allergy. A role for lipids in enhancing allergenic potency has been described in peach 3 and cow's milk allergies.…”