Increased Risk for Malignancies in 131 Affected CTLA4 Mutation Carriers

Abstract

<b>Background:</b> Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a negative immune regulator on the surface of T cells. In humans, heterozygous germline mutations in <i>CTLA4</i> can cause an immune dysregulation syndrome. The phenotype comprises a broad spectrum of autoinflammatory, autoimmune, and immunodeficient features. An increased frequency of malignancies in primary immunodeficiencies is known, but their incidence in CTLA-4 insufficiency is unknown. <b>Methods:</b> Clinical manifestations and details of the clinical history were assessed in a worldwide cohort of 184 <i>CTLA4</i> mutation carriers. Whenever a malignancy was reported, a malignancy-specific questionnaire was filled. <b>Results:</b> Among the 184 <i>CTLA4</i> mutation carriers, 131 were considered affected, indicating a penetrance of 71.2%. We documented 17 malignancies, which amounts to a cancer prevalence of 12.9% in affected <i>CTLA4</i> mutation carriers. There were ten lymphomas, five gastric cancers, one multiple myeloma, and one metastatic melanoma. Seven lymphomas and three gastric cancers were EBV-associated. <b>Conclusion:</b> Our findings demonstrate an elevated cancer risk for patients with CTLA-4 insufficiency. As more than half of the cancers were EBV-associated, the failure to control oncogenic viruses seems to be part of the CTLA-4-insufficient phenotype. Hence, lymphoproliferation and EBV viral load in blood should be carefully monitored, especially when immunosuppressing affected <i>CTLA4</i> mutation carriers.