AUTHOR=Egg David , Schwab Charlotte , Gabrysch Annemarie , Arkwright Peter D. , Cheesman Edmund , Giulino-Roth Lisa , Neth Olaf , Snapper Scott , Okada Satoshi , Moutschen Michel , Delvenne Philippe , Pecher Ann-Christin , Wolff Daniel , Kim Yae-Jean , Seneviratne Suranjith , Kim Kyoung-Mee , Kang Ji-Man , Ojaimi Samar , McLean Catriona , Warnatz Klaus , Seidl Maximilian , Grimbacher Bodo
TITLE=Increased Risk for Malignancies in 131 Affected CTLA4 Mutation Carriers
JOURNAL=Frontiers in Immunology
VOLUME=9
YEAR=2018
URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.02012
DOI=10.3389/fimmu.2018.02012
ISSN=1664-3224
ABSTRACT=Background: 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 CTLA4 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.
Methods: Clinical manifestations and details of the clinical history were assessed in a worldwide cohort of 184 CTLA4 mutation carriers. Whenever a malignancy was reported, a malignancy-specific questionnaire was filled.
Results: Among the 184 CTLA4 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 CTLA4 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.
Conclusion: 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 CTLA4 mutation carriers.