Project description: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 and 21 additional patients with targeted sequencing. The Cancer Genome Atlas (TCGA) 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 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. Tumor progression was associated with upregulation of cell cycle progression, migration, and DNA damage repair-related genes. The cell cycle checkpoint genes CDKN2A or RB1 were most commonly inactivated, followed by activating growth factor receptor gene alterations in cases with homozygous CDKN2A deletion. We also detected progression-related alterations in DNA repair pathway genes associated with the promotion of error-prone DNA repair, thus facilitating tumor progression. The homologous recombination repair gene RAD51B was hemizygously deleted in all but one progressed tumor in our discovery cohort. In our retrospective analysis of patient treatment and survival timelines, the combination of postoperative radiation and chemotherapy (mainly temozolomide) outperformed radiation especially in the grade 3 tumor cohort, in which it was typically given after primary surgery. Our results support previous notions that treatment contributes to tumor evolution and suggest that altered DNA repair has a role in treatment resistance and tumor progression.

Dataset Information

DNA methylation and somatic mutations converge on cell cycle and define similar evolutionary histories in brain tumors

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure