A Patient with CTLA-4 Haploinsufficiency Presenting Gastric Cancer
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Cytotoxic T-lymphocyte-antigen 4 (CTLA-4) is an essential negative regulator expressed on regulatory T cells (Tregs) and activated T cells. Germline heterozygous mutations in CTLA4 lead to haploinsufficiency of CTLA-4, resulting in the development of an autosomal dominant immune dysregulation syndrome with incomplete penetrance. We report here a Japanese patient with this disorder who has a novel heterozygous single nucleotide insertion, 76_77insT (p. L28SfsX40), in the CTLA4 gene. Peripheral blood mononuclear cells from the patient showed decreased frequency of CTLA-4high cells in CD4+FOXP3+ cells following CD3/CD28 stimulation. The patient experienced hypogammaglobulinemia, recurrent pneumonia, esophageal candidiasis, cytomegalovirus-positive chronic gastritis, chronic and severe diarrhea, and type 1 diabetes mellitus. Moreover, the patient developed multifocal gastric cancer, histologically poorly and well-differentiated adenocarcinomas, associated with chronic atrophic gastritis and intestinal metaplasia. Previously, 23 symptomatic cases with heterozygous CTLA4 mutations have been reported. Including the case presented here, 3 of the 24 cases (12.5 %) developed gastric cancer. Notably, 2 of 3 patients presented similarly multifocal adenocarcinomas associated with atrophic gastritis and intestinal metaplasia. Predisposition to gastric cancer has been also reported in CVID patients. These clinical observations suggest that gastric cancer is a disease commonly associated with autosomal dominant immune dysregulation syndrome due to CTLA4 mutation.
KeywordsCTLA-4 FOXP3 Autosomal dominant immune dysregulation syndrome Gastric cancer Regulatory T cells
Sequence analysis was supported by the Analysis Center of Life Science, Natural Science Center for Basic Research and Development, Hiroshima University (Hiroshima, Japan). This study was supported in part by Grants in Aid for Scientific Research from the Japan Society for the Promotion of Science [25293231 to M.K.], [26670501 to M.K.], [25713039 to S.O.], and [25670477 to S.O.]. This study was also supported in part by Research on Measures for Intractable Diseases funding from the Japanese Ministry of Health, Labour and Welfare [201324051A to M.K.] and [201324062A to M.K.].
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