Abstract:
Despite rapid advances in the field of immunotherapy, including the success of immune checkpoint inhibition in treating multiple cancer types, clinical response in high-grade gliomas (HGGs) has been disappointing. This has been in part attributed to the low tumor mutational burden (TMB) of the majority of HGGs. Hypermutation is a recently characterized glioma signature that occurs in a small subset of cases, which may open an avenue to immunotherapy. The substantially elevated TMB of these tumors most commonly results from alterations in the DNA mismatch repair pathway in the setting of extensive exposure to temozolomide or, less frequently, from inherited cancer predisposition syndromes. In this review, we discuss the genetics and etiology of hypermutation in HGGs, with an emphasis on the resulting genomic signatures, and the state and future directions of immuno-oncology research in these patient populations.
摘要:
尽管在免疫治疗领域取得了快速进展,包括免疫检查点抑制在治疗多种癌症中的成功,高级别胶质瘤(HGG)的临床反应令人失望。这部分归因于大多数HGs的低肿瘤突变负荷(TMB)。超突变是一种最近表征的神经胶质瘤特征,发生在一小部分病例中,这可能为免疫疗法开辟了一条途径。这些肿瘤的显著升高的TMB最常见的原因是在广泛暴露于替莫唑胺或,不那么频繁,来自遗传性癌症易感性综合症。在这次审查中,我们讨论了HGs超突变的遗传学和病因学,强调产生的基因组特征,以及这些患者人群中免疫肿瘤学研究的状态和未来方向。