A Patient with CTLA-4 Haploinsufficiency Presenting Gastric Cancer

Abstract

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-4(high) 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.

Genes associated with common variable immunodeficiency: one diagnosis to rule them all?

“…Most CTLA4 mutations resulted in reduced CTLA-4 expression suggesting haploinsufficiency 60 61 73 74. Other CTLA4 mutations were predicted to interfere with ligand binding or protein stability, which might exert a dominant-negative effect 61.…”

“…Other CTLA4 mutations were predicted to interfere with ligand binding or protein stability, which might exert a dominant-negative effect 61. Many CTLA-4-deficient patients were clinically diagnosed with CVID 60 61 73 74. However, CTLA4 mutations were also detected in family members who were asymptomatic or had sIgAD, pointing to incomplete penetrance 60 61 73 74.…”

“…Many CTLA-4-deficient patients were clinically diagnosed with CVID 60 61 73 74. However, CTLA4 mutations were also detected in family members who were asymptomatic or had sIgAD, pointing to incomplete penetrance 60 61 73 74. Alternatively, the phenotype may be modulated by other disease-modifying genes and/or environmental influences.…”

CHAI and LATAIE: new genetic diseases of CTLA-4 checkpoint insufficiency

“…The frequency of patients with interstitial lung disease may potentially be higher for LATAIE disease in which patients are frequently described with chronic lung disease and/or digital clubbing, but interstitial lung disease was not always documented. 6,7,16 Furthermore, disease penetrance can vary. Penetrance for CHAI disease is incomplete, with an estimated 40% of CTLA4 mutation-positive family members appearing clinically healthy.…”

“…The majority of CTLA4 reported mutations causing CHAI resulted in loss of protein expression and include insertions/deletions (frameshift), nonsense, missense, splicing mutations, and 1 substitution mutation disrupting the start codon ( Figure 1B). 4,5,16 Two mutations led to alternative splicing, which removed the transmembrane domain resulting in soluble CTLA-4 rather than the more functional membrane-bound form ( Figure 1B). 4 Two missense mutations appeared to interfere with ligand binding.…”