Baranwal Anmol, Hahn Christopher N, Shah Mithun Vinod, Hiwase Devendra K
Division of Hematology, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55906, USA.
Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.
Curr Hematol Malig Rep. 2022 Dec;17(6):254-265. doi: 10.1007/s11899-022-00676-2. Epub 2022 Aug 20.
Therapy-related myeloid neoplasms (t-MNs) are aggressive leukemias that develop following exposure to DNA-damaging agents. A subset of patients developing t-MN may have an inherited susceptibility to develop myeloid neoplasia. Herein, we review studies reporting t-MN and their association with a germline or inherited predisposition.
Emerging evidence suggests that development of t-MN is the result of complex interactions including generation of somatic variants in hematopoietic stem cells and/or clonal selection pressure exerted by the DNA-damaging agents, and immune evasion on top of any inherited genetic susceptibility. Conventionally, alkylating agents, topoisomerase inhibitors, and radiation have been associated with t-MN. Recently, newer modalities including poly (ADP-ribose) polymerase inhibitors (PARPi) and peptide receptor radionucleotide therapy (PRRT) are associated with t-MN. At the same time, the role of pathogenic germline variants (PGVs) in genes such as BRCA1/2, BARD1, or TP53 on the risk of t-MN is being explored. Moreover, studies have shown that while cytotoxic therapy increases the risk of developing myeloid neoplasia, it may be exposing the vulnerability of an underlying germline predisposition. t-MN remains a disease with poor prognosis. Studies are needed to better define an individual's inherited neoplastic susceptibility which will help predict the risk of myeloid neoplasia in the future. Understanding the genes driving the inherited neoplastic susceptibility will lead to better patient- and cancer-specific management including choice of therapeutic regimen to prevent, or at least delay, development of myeloid neoplasia after treatment of a prior malignancy.
治疗相关髓系肿瘤（t-MN）是在接触DNA损伤剂后发生的侵袭性白血病。一部分发生t-MN的患者可能具有发生髓系肿瘤的遗传易感性。在此，我们综述了报告t-MN及其与种系或遗传易感性关联的研究。
新出现的证据表明，t-MN的发生是复杂相互作用的结果，包括造血干细胞中体细胞变异的产生和/或DNA损伤剂施加的克隆选择压力，以及在任何遗传易感性之上的免疫逃逸。传统上，烷化剂、拓扑异构酶抑制剂和辐射与t-MN有关。最近，包括聚（ADP-核糖）聚合酶抑制剂（PARPi）和肽受体放射性核素治疗（PRRT）在内的新疗法也与t-MN有关。同时，正在探索BRCA1/2、BARD1或TP53等基因中的致病种系变异（PGV）对t-MN风险的作用。此外，研究表明，虽然细胞毒性疗法会增加发生髓系肿瘤的风险，但它可能暴露了潜在种系易感性的脆弱性。t-MN仍然是一种预后不良的疾病。需要开展研究以更好地界定个体的遗传性肿瘤易感性，这将有助于预测未来髓系肿瘤的风险。了解驱动遗传性肿瘤易感性的基因将带来更好的针对患者和癌症的管理，包括选择治疗方案以预防或至少延迟先前恶性肿瘤治疗后髓系肿瘤的发生。
