Cancer Immunomonitoring and Immuno-Mediated Pathologies Support Unit, IdSSC, Department of Clinical Immunology, San Carlos Clinical Hospital, Madrid, Spain.
Department of Clinical Immunology, IML and IdSSC, San Carlos Clinical Hospital, Madrid, Spain.
Front Immunol. 2022 Aug 5;13:937872. doi: 10.3389/fimmu.2022.937872. eCollection 2022.
Common variable immunodeficiency (CVID) represents the largest group of primary immunodeficiencies that may manifest with infections, inflammation, autoimmunity, and cancer, mainly B-cell non-Hodgkin's lymphoma (NHL). Indeed, NHL may result from chronic or recurrent infections and has, therefore, been recognized as a clinical phenotype of CVID, although rare. The more one delves into the mechanisms involved in CVID and cancer, the stronger the idea that both pathologies can be a reflection of the same primer events observed from different angles. The potential effects of germline variants on specific somatic modifications in malignancies suggest that it might be possible to anticipate critical events during tumor development. In the same way, a somatic alteration in NHL could be conditioning a similar response at the transcriptional level in the shared signaling pathways with genetic germline alterations in CVID. We aimed to explore the genomic substrate shared between these entities to better characterize the CVID phenotype immunodeficiency in NHL. By means of an approach, we interrogated the large, publicly available datasets contained in cBioPortal for the presence of genes associated with genetic pathogenic variants in a panel of 50 genes recurrently altered in CVID and previously described as causative or disease-modifying. We found that 323 (25%) of the 1,309 NHL samples available for analysis harbored variants of the CVID spectrum, with the most recurrent alteration presented in NHL occurring in PIK3CD (6%) and STAT3 (4%). Pathway analysis of common gene alterations showed enrichment in inflammatory, immune surveillance, and defective DNA repair mechanisms similar to those affected in CVID, with PIK3R1 appearing as a central node in the protein interaction network. The co-occurrence of gene alterations was a frequent phenomenon. This study represents an attempt to identify common genomic grounds between CVID and NHL. Further prospective studies are required to better know the role of genetic variants associated with CVID and their reflection on the somatic pathogenic variants responsible for cancer, as well as to characterize the CVID-like phenotype in NHL, with the potential to influence early CVID detection and therapeutic management.
普通变异性免疫缺陷（CVID）是最大的一组原发性免疫缺陷，可能表现为感染、炎症、自身免疫和癌症，主要是非霍奇金淋巴瘤（NHL）。事实上，NHL 可能源于慢性或复发性感染，因此被认为是 CVID 的一种临床表型，尽管很少见。人们对 CVID 和癌症相关机制的研究越深入，就越能认识到这两种疾病可能是同一基本事件从不同角度观察的结果。种系变异对恶性肿瘤特定体细胞改变的潜在影响表明，有可能预测肿瘤发展过程中的关键事件。同样，NHL 的体细胞改变可能会使 CVID 遗传种系改变相关的信号通路中的转录水平产生类似的反应。我们旨在探索这些实体之间共享的基因组基础，以更好地描述 NHL 中 CVID 表型免疫缺陷。通过一种 方法，我们在 cBioPortal 中查询了大型公共可用数据集，以确定与 CVID 中一组 50 个经常改变的基因相关的基因是否存在遗传致病性变异，这些基因先前被描述为致病或疾病修饰。我们发现，可用于分析的 1309 个 NHL 样本中有 323 个（25%）存在 CVID 谱中的变异，NHL 中最常见的改变发生在 PIK3CD（6%）和 STAT3（4%）。常见基因改变的途径分析显示，在 CVID 中受到影响的炎症、免疫监视和 DNA 修复缺陷机制中存在富集，PIK3R1 作为蛋白质相互作用网络中的中心节点出现。基因改变的共发生是一种常见现象。这项研究代表了在 CVID 和 NHL 之间确定共同基因组基础的尝试。需要进一步的前瞻性研究来更好地了解与 CVID 相关的遗传变异及其对导致癌症的体细胞致病性变异的影响，并描述 NHL 中的 CVID 样表型，这有可能影响早期 CVID 的检测和治疗管理。
