由于低度弥漫性星形细胞瘤进展为 4 级肿瘤会显着影响患者预后，因此更好地了解这一过程对于改善患者护理至关重要。在该项目中，我们分析了 6 名患者（发现队列）进行全基因组测序、另外 21 名进行靶向测序的患者以及来自胶质瘤纵向 AnalySiS 队列的 33 名患者在进展为 4 级之前和之后的匹配 IDH 突变星形细胞瘤以进行验证。来自 595 个弥漫性神经胶质瘤的癌症基因组图谱数据提供了支持信息。我们的发现队列中的所有患者均接受了放疗，除一名患者外均接受了化疗，并且没有患者在进展为 4 级疾病之前接受了替莫唑胺 (TMZ)。发现队列中的一个病例表现出与 MSH2 和 DNMT3A 基因失活相关的超突变特征。在其他患者中，4 级肿瘤中染色体重排和缺失的数量有所增加。与其他治疗组相比，接受化疗和放疗后，细胞周期检查点基因 CDKN2A（或频率较低的 RB1）最常见失活。在获得纯合 CDKN2A 缺失的肿瘤中检测到伴随的激活 PDGFRA/MET 改变。 NRG3 基因在进展性肿瘤中显着下调并反复改变。在单变量和多变量分析中，其表达减少与较差的总生存率相关。我们还检测到 RAD51B 和其他 DNA 修复途径基因中与进展相关的改变，这些改变与促进易错 DNA 修复相关，可能促进肿瘤进展。在我们对患者治疗和生存时间的回顾性分析中（n = 75），术后放疗和化疗（主要是 TMZ）的组合优于放疗，尤其是在 3 级肿瘤队列中，通常在初次手术后给予。我们的结果进一步深入了解治疗和细胞周期遗传改变、生长因子信号传导和 DNA 修复相关基因对肿瘤进化和进展的贡献。© 2023。作者。

As the progression of low-grade diffuse astrocytomas into grade 4 tumors significantly impacts patient prognosis, a better understanding of this process is of paramount importance for improved patient care. In this project, we analyzed matched IDH-mutant astrocytomas before and after progression to grade 4 from six patients (discovery cohort) with genome-wide sequencing, 21 additional patients with targeted sequencing, and 33 patients from Glioma Longitudinal AnalySiS cohort for validation. The Cancer Genome Atlas data from 595 diffuse gliomas provided supportive information. All patients in our discovery cohort received radiation, all but one underwent chemotherapy, and no patient received temozolomide (TMZ) before progression to grade 4 disease. One case in the discovery cohort exhibited a hypermutation signature associated with the inactivation of the MSH2 and DNMT3A genes. In other patients, the number of chromosomal rearrangements and deletions increased in grade 4 tumors. The cell cycle checkpoint gene CDKN2A, or less frequently RB1, was most commonly inactivated after receiving both chemo- and radiotherapy when compared to other treatment groups. Concomitant activating PDGFRA/MET alterations were detected in tumors that acquired a homozygous CDKN2A deletion. NRG3 gene was significantly downregulated and recurrently altered in progressed tumors. Its decreased expression was associated with poorer overall survival in both univariate and multivariate analysis. We also detected progression-related alterations in RAD51B and other DNA repair pathway genes associated with the promotion of error-prone DNA repair, potentially facilitating tumor progression. In our retrospective analysis of patient treatment and survival timelines (n = 75), the combination of postoperative radiation and chemotherapy (mainly TMZ) outperformed radiation, especially in the grade 3 tumor cohort, in which it was typically given after primary surgery. Our results provide further insight into the contribution of treatment and genetic alterations in cell cycle, growth factor signaling, and DNA repair-related genes to tumor evolution and progression.© 2023. The Author(s).