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

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.

PTPRD and CNTNAP2 as markers of tumor aggressiveness in oligodendrogliomas.

Oligodendrogliomas are typically associated with the most favorable prognosis among diffuse gliomas. However, many of the tumors progress, eventually leading to patient death. To characterize the changes associated with oligodendroglioma recurrence and progression, we analyzed two recurrent oligodendroglioma tumors upon diagnosis and after tumor relapse based on whole-genome and RNA sequencing. Relapsed tumors were diagnosed as glioblastomas with an oligodendroglioma component before the World Health Organization classification update in 2016. Both patients died within 12 months after relapse. One patient carried an inactivating POLE mutation leading to a clearly hypermutated progressed tumor. Strikingly, both relapsed tumors carried focal chromosomal rearrangements in PTPRD and CNTNAP2 genes with associated decreased gene expression. TP53 mutation was also detected in both patients after tumor relapse. In The Cancer Genome Atlas (TCGA) diffuse glioma cohort, PTPRD and CNTNAP2 expression decreased by tumor grade in oligodendrogliomas and PTPRD expression also in IDH-mutant astrocytomas. Low expression of the genes was associated with poor overall survival. Our analysis provides information about aggressive oligodendrogliomas with worse prognosis and suggests that PTPRD and CNTNAP2 expression could represent an informative marker for their stratification.