Abstract
BackgroundLipopolysaccharide-responsive, beige-like anchor protein (LRBA) deficiency is characterized by primary immunodeficiency and autoimmunity. Cancer may present another feature of LRBA deficiency. We describe a case history of a young adult with LRBA deficiency and two independent malignancies.MethodsFamily-trio whole exome sequencing with unbiased phenotype ontology approach was used for identification of causative mutations of a primary immune deficiency disorder. Additionally, we sought to identify germline mutations in genes known to be associated with two independent malignancies using a targeted approach. A cytotoxic T-lymphocyte associated protein 4 (CTLA4) expression in T lymphocytes was determined by flow cytometry.ResultsIn the patient with clinical signs of LRBA deficiency multifocal gastric carcinoma and malignant melanoma were diagnosed and surgically treated at 19 and 27 years of age, respectively. Despite refusal of any adjuvant chemotherapy or radiotherapy, the patient demonstrated disease free survival for at least 13 years after the first cancer diagnosis. A homozygous frameshift deletion in LRBA gene (p.Glu946Ter) and two common variants in TYR gene were identified. Reduced CTLA4 expression in a subset of regulatory T lymphocytes was identified in the patient and his unaffected mother carrying a heterozygous LRBA mutation as compared to control in a dose-dependent manner.ConclusionThis is the first description of gastric cancer and malignant melanoma in a young adult with LRBA deficiency. The role of LRBA gene knockout in cancer development and its prognosis remains to be elucidated.
Highlights
Lipopolysaccharide-responsive, beige-like anchor protein (LRBA) deficiency is characterized by primary immunodeficiency and autoimmunity
Genes associated with inherited susceptibility to malignant melanoma (CDKN2A, MDM2, CDK4, RB1, MC1R, tyrosinase gene (TYR), TYRP1 and ASIP) [20], gastric cancer (CDH1, CTNNA1, BRCA1, BRCA2, APC, TP53, STK11, SMAD4, BMPR1A, MSH2, MLH1) [21], and Cytotoxic T-lymphocyte associated protein 4 (CTLA4) gene were analyzed with targeted approach
Parents are distant relatives; the patient’s great grandmother and great grandfather were first cousins. In support to their distant relation larger stretches of Loss of Heterozygosity (LoH) regions were identified at chromosomes 2, 5 and 6 (Additional file 2: Figure S2)
Summary
Lipopolysaccharide-responsive, beige-like anchor protein (LRBA) deficiency is characterized by primary immunodeficiency and autoimmunity. Cancer may present another feature of LRBA deficiency. We describe a case history of a young adult with LRBA deficiency and two independent malignancies. Deleterious germline mutations in LRBA gene encoding lipopolysaccharide-responsive, beige-like anchor protein (LRBA) have been recently associated with an autosomal recessive monogenic disorder, whose common denominators are LRBA deficiency, Autoimmunity, regulatory T (Treg) cell defects, Autoimmune Infiltration, and Enteropathy (LATAIE syndrome) [1,2,3,4,5]. Immunologic, and genetic characteristics of a patient with a novel pathogenic homozygous LRBA gene mutation presenting with immune deficiency and multiorgan autoimmunity, and with two independent malignant diseases. The presented clinical spectrum recapitulates and extends the previously described phenotypes.
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