Bratanič Nina, Kovač Jernej, Pohar Katka, Trebušak Podkrajšek Katarina, Ihan Alojz, Battelino Tadej, Avbelj Stefanija Magdalena
Department of Pediatric Endocrinology, Diabetes and Metabolism, University Medical Centre, University Children's Hospital, Bohoriceva 20, 1000, Ljubljana, Slovenia.
University Medical Centre, University Children's Hospital, Unit for Special Laboratory Diagnostics, Vrazov trg 1, 1000, Ljubljana, Slovenia.
Orphanet J Rare Dis. 2017 Jul 18;12(1):131. doi: 10.1186/s13023-017-0682-5.
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.
Family-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.
In 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.
This 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.
脂多糖反应性米色样锚定蛋白（LRBA）缺乏症的特征为原发性免疫缺陷和自身免疫。癌症可能是LRBA缺乏症的另一特征。我们描述了一名患有LRBA缺乏症且患两种独立恶性肿瘤的年轻成年人的病例史。
采用家族三联全外显子测序及无偏倚表型本体论方法来鉴定原发性免疫缺陷疾病的致病突变。此外，我们试图采用靶向方法鉴定已知与两种独立恶性肿瘤相关基因中的种系突变。通过流式细胞术测定T淋巴细胞中细胞毒性T淋巴细胞相关蛋白4（CTLA4）的表达。
在患有LRBA缺乏症临床体征的患者中，分别于19岁和27岁诊断出多灶性胃癌和恶性黑色素瘤并接受了手术治疗。尽管拒绝接受任何辅助化疗或放疗，但该患者在首次癌症诊断后至少13年无病生存。在LRBA基因中鉴定出纯合移码缺失（p.Glu946Ter），在TYR基因中鉴定出两个常见变异。与对照组相比，在患者及其携带杂合LRBA突变的未受影响母亲中，调节性T淋巴细胞亚群中CTLA4表达呈剂量依赖性降低。
这是首次描述患有LRBA缺乏症的年轻成年人患胃癌和恶性黑色素瘤的情况。LRBA基因敲除在癌症发生发展及其预后中的作用仍有待阐明。
