Genomic characterization of IDH-mutant astrocytoma progression to grade 4 in the treatment setting

Abstract

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.

Pyrosequencing Analysis of O-6-Methylguanine-DNA Methyltransferase Methylation at Different Cut-Offs of Positivity Associated with Treatment Response and Disease-Specific Survival in Isocitrate Dehydrogenase-Wildtype Grade 4 Glioblastoma

“…This could make a complete difference when it comes to survival profiles since grade 4 astrocytomas are tumors with better prognostic factors than GBMs [ 10 , 38 , 39 , 40 ]. In our study, for example, the aggressiveness of these types of tumors can be seen when we observe that, after the follow-up period up to November 2023, only 12.8% of the 78 patients were alive.…”

“…Therefore, our study analyzed the prognostic and survival values associated with this group of patients at different cut-offs. Three different cut-off points were used, two according to the literature at 5% and 9% [ 34 , 35 , 36 , 37 , 38 , 39 ] and a third at 11% [ 55 ]. The values of 8% and 10%, also quite common in the literature, were excluded due to the small difference in the number of patients between these groups and the 9% group.…”

“…The methylation status of MGMT was 51.3% (40) methylated and 48.7% (38) unmethylated (Table 2). Considering TR, of the 38 unmethylated patients, 100% (38) presented progressive disease, while in the 40 methylated patients, this number dropped to 80% (32) (p < 0.001) (Figure 4B).…”