Allergy and Clinical Immunology Unit, Division of Rheumatology, Allergy, & Immunology, Massachusetts General Hospital, Boston, Mass.
Research Department, Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus.
J Allergy Clin Immunol Pract. 2022 Jul;10(7):1725-1736.e2. doi: 10.1016/j.jaip.2022.03.012. Epub 2022 Mar 29.
Inborn errors of immunity (IEI) are genetically and clinically heterogeneous disorders that, in addition to infection susceptibility and immune dysregulation, can have an enhanced cancer predisposition. The increasing availability of upfront next-generation sequencing diagnostics in immunology and oncology have uncovered substantial overlap of germline and somatic genetic conditions that can result in immunodeficiency and cancer. However, broad application of unbiased genetics in these neighboring disciplines still needs to be deployed, and joined therapeutic strategies guided by germline and somatic genetic risk factors are lacking. We illustrate the current difficulties encountered in clinical practice, summarize the historical development of pathophysiological concepts of cancer predisposition, and review select genetic, molecular, and cellular mechanisms of well-defined and illustrative disease entities such as DNA repair defects, combined immunodeficiencies with Epstein-Barr virus susceptibility, autoimmune lymphoproliferative syndromes, regulatory T-cell disorders, and defects in cell intrinsic immunity. We review genetic variants that, when present in the germline, cause IEI with cancer predisposition but, when arising as somatic variants, behave as oncogenes and cause specific cancer entities. We finally give examples of small molecular compounds that are developed and studied to target genetically defined cancers but might also proof useful to treat IEI.
先天性免疫缺陷（IEI）是一种遗传和临床异质性疾病，除了感染易感性和免疫失调外，还可能具有增强的癌症易感性。免疫学和肿瘤学中高通量测序诊断技术的不断发展，揭示了大量可导致免疫缺陷和癌症的种系和体细胞遗传状况的重叠。然而，广泛应用于这些相邻学科的无偏遗传学仍然需要部署，并且缺乏基于种系和体细胞遗传风险因素的联合治疗策略。我们举例说明了在临床实践中遇到的当前困难，总结了癌症易感性的病理生理学概念的历史发展，并回顾了明确和具有代表性的疾病实体的特定遗传、分子和细胞机制，如 DNA 修复缺陷、伴有 EBV 易感性的联合免疫缺陷、自身免疫性淋巴增生综合征、调节性 T 细胞疾病以及细胞内固有免疫缺陷。我们回顾了在种系中存在时导致具有癌症易感性的 IEI 的遗传变异，但当作为体细胞变异出现时，这些变异会表现为致癌基因并导致特定的癌症实体。最后，我们给出了一些小分子化合物的例子，这些化合物是为了针对遗传定义的癌症而开发和研究的，但也可能对治疗 IEI 有用。
