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Increased Risk for Malignancies in 131 Affected CTLA4 Mutation Carriers

 David Egg  ;  Charlotte Schwab  ;  Annemarie Gabrysch  ;  Peter D. Arkwright  ;  Edmund Cheesman  ;  Lisa Giulino-Roth  ;  Olaf Neth  ;  Scott Snapper  ;  Satoshi Okada  ;  Michel Moutschen  ;  Philippe Delvenne  ;  Ann-Christin Pecher  ;  Daniel Wolff  ;  Yae-Jean Kim  ;  Suranjith Seneviratne  ;  Kyoung-Mee Kim  ;  Ji-Man Kang  ;  Samar Ojaimi  ;  Catriona McLean  ;  Klaus Warnatz  ;  Maximilian Seidl  ;  Bodo Grimbacher 
 FRONTIERS IN IMMUNOLOGY, Vol.9 : 2012, 2018 
Journal Title
Issue Date
CMV ; CTLA4 ; EBV ; cancer predisposition ; combined immunodeficiency ; malignancy ; primary immunodeficiency
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.
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1. College of Medicine (의과대학) > Dept. of Pediatrics (소아과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Ji-Man(강지만) ORCID logo https://orcid.org/0000-0002-0678-4964
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