Journal Article

Increased Risk for Malignancies in 131 Affected CTLA4 Mutation Carriers

Seneviratne, Suranjith, Warnatz, Klaus, Cheesman, Edmund, Pecher, Ann-Christin, Kim, Kyoung-Mee, Kang, Ji-Man, Delvenne, Philippe, Okada, Satoshi, Neth, Olaf, Schwab, Charlotte, Moutschen, Michel, Grimbacher, Bodo, Ojaimi, Samar, Kim, Yae-Jean, Giulino-Roth, Lisa, Wolff, Daniel, Egg, David, Gabrysch, Annemarie, Arkwright, Peter D., Snapper, Scott, McLean, Catriona, Seidl, Maximilian

2018

Overview

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 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. Clinical manifestations and details of the clinical history were assessed in a worldwide cohort of 184 mutation carriers. Whenever a malignancy was reported, a malignancy-specific questionnaire was filled. Among the 184 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 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. 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 mutation carriers.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Adenocarcinoma - epidemiology / Adenocarcinoma - genetics / Adolescent / Adult / Age / Aged / Cancer predisposition / Cancer therapies / Chemotherapy / CMV / Cohort Studies / Combined immunodeficiency / CTLA-4 Antigen - genetics / CTLA-4 protein / CTLA4 / Cytotoxicity / EBV / Epstein-Barr Virus Infections - epidemiology / Female / Females / Gastric cancer / Gastrointestinal surgery / Herpesvirus 4, Human - physiology / Human health sciences / Humans / Immune system / Immunodeficiency / Immunologie & maladie infectieuse / Immunology / Immunology & infectious disease / Lymphocytes / Lymphocytes T / Lymphoma / Lymphoma - epidemiology / Lymphoma - genetics / Male / Malignancy / Medical diagnosis / Melanoma / Metastases / Metastasis / Middle Aged / Multiple myeloma / Mutation / Mutation - genetics / Patients / Phenotypes / Prevalence / Primary immunodeficiencies / Primary immunodeficiency / Remission (Medicine) / Risk / Sciences de la santé humaine / Stomach Neoplasms - epidemiology / Stomach Neoplasms - genetics / Young Adult