Department of Allergology and Clinical Immunology, Faculty of Medicine, Charles University and University Hospital in Hradec Kralove, Hradec Kralove, Czechia.
Department of Immunology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czechia.
Front Immunol. 2019 Jan 22;9:3135. doi: 10.3389/fimmu.2018.03135. eCollection 2018.
Common variable immunodeficiency disorder (CVID) is one of the most frequent inborn errors of immunity, increased occurrence of malignancies, particularly lymphomas, and gastric cancers, has long been noted among CVID patients. Multifactorial etiology, including immune dysregulation, infections, chronic inflammation, or genetic background, is suggested to contribute to tumor development. Here, we present the results of the first Czech nationwide study focused on epidemiology, immunology and genetic background in a cohort of CVID patients who also developed tumors The cohort consisted of 295 CVID patients followed for 3,070 patient/years. Standardized incidence ratio (SIR) was calculated to determine the risk of cancer, and Risk ratio (RR) was established to evaluate the significance of comorbidities. Moreover, immunophenotyping, including immunoglobulin levels and lymphocyte populations, was assessed. Finally, Whole exome sequencing (WES) was performed in all patients with lymphoma to investigate the genetic background. Twenty-five malignancies were diagnosed in 22 patients in a cohort of 295 CVID patients. SIR was more than 6 times greater in comparison to the general population. The most common neoplasias were gastric cancers and lymphomas. History of Immune thrombocytopenic purpura (ITP) was established as a potential risk factor, with over 3 times higher risk of cancer development. The B cell count at diagnosis of lymphoma was reduced in the lymphoma group; moreover, post-treatment B and T cell lymphopenia, associated with poorer outcome, was found in a majority of the patients. Intriguingly, no NK cell depression was observed after the chemotherapy. WES revealed heterogeneous genetic background among CVID patients with tumors, identifying gene variants associated with primary immunodeficiencies (such as CTLA4, PIK3CD, PMS2) and/or increased cancer susceptibility (including BRCA1, RABEP1, EP300, KDM5A). The incidence of malignancy in our CVID cohort was found to be more than 6 times greater compared to the general population. Gastric cancers and lymphomas were the most frequently diagnosed tumors. ITP was identified as a risk factor for malignancy in CVID patients. WES analysis confirmed a wide genetic heterogeneity among CVID patients. The identified causative or modifying gene variants pointed to errors in mechanisms contributing to both immunodeficiency and malignancy.
普通变异型免疫缺陷病（CVID）是最常见的先天性免疫缺陷之一，CVID 患者中恶性肿瘤，特别是淋巴瘤和胃癌的发病率增加，这一现象由来已久。多种病因，包括免疫失调、感染、慢性炎症或遗传背景，被认为有助于肿瘤的发展。在这里，我们报告了捷克首例全国性研究的结果，该研究关注的是一组发生肿瘤的 CVID 患者的流行病学、免疫学和遗传背景。该队列包括 295 名接受 3070 患者/年随访的 CVID 患者。通过计算标准化发病比（SIR）来确定癌症的风险，并通过风险比（RR）来评估合并症的意义。此外，还评估了免疫表型，包括免疫球蛋白水平和淋巴细胞群。最后，对所有患有淋巴瘤的患者进行了全外显子组测序（WES），以研究遗传背景。在 295 名 CVID 患者的队列中，有 22 名患者被诊断出 25 种恶性肿瘤。与普通人群相比，SIR 高出 6 倍以上。最常见的肿瘤是胃癌和淋巴瘤。免疫性血小板减少性紫癜（ITP）病史被确定为潜在的危险因素，癌症发展的风险高出 3 倍以上。淋巴瘤组的淋巴瘤诊断时 B 细胞计数降低；此外，大多数患者在治疗后出现 B 和 T 淋巴细胞减少症，与预后较差相关。有趣的是，化疗后未观察到 NK 细胞抑制。WES 显示肿瘤 CVID 患者的遗传背景具有异质性，鉴定出与原发性免疫缺陷（如 CTLA4、PIK3CD、PMS2）和/或癌症易感性增加（包括 BRCA1、RABEP1、EP300、KDM5A）相关的基因变异。我们发现，CVID 队列中的恶性肿瘤发病率与普通人群相比高出 6 倍以上。胃癌和淋巴瘤是最常见的诊断肿瘤。ITP 被确定为 CVID 患者恶性肿瘤的危险因素。WES 分析证实 CVID 患者之间存在广泛的遗传异质性。鉴定出的致病或修饰基因变异表明，导致免疫缺陷和恶性肿瘤的机制存在错误。
