P10.14.B PROGRESSION OF IDH-MUTANT ASTROCYTOMAS TO GRADE 4 UNDER TREATMENT-RELATED SELECTION PRESSURE

Abstract BACKGROUND The progression of low-grade diffuse astrocytomas into grade 4 tumors significantly impacts patient prognosis, therefore a better understanding of this process is of paramount importance for improved patient care. MATERIAL AND METHODS We analyzed next-generation sequencing data from matched IDH-mutant astrocytomas before and after progression to grade 4 from up to 27 patients as well as publicly available The Cancer Genome Atlas (TCGA) data from up to 595 cases. All patients in our discovery cohort with genome-wide sequencing data received radiation, all but one underwent chemotherapy, and no patient received temozolomide before progression to grade 4. RESULTS One case in the discovery cohort exhibited a hypermutation signature associated with inactivation of the MSH2 and DNMT3A genes. In other patients, the number of novel chromosomal rearrangements and deletions increased in grade 4 tumors. Tumor progression was associated with upregulated cell cycle progression, migration, and DNA damage repair-related genes. Upon progression, the cell cycle checkpoint genes CDKN2A or RB1 were most commonly inactivated, especially after postoperative radiation and chemotherapy, followed by activating growth factor receptor gene alterations in cases with homozygous CDKN2A deletion. We also detected alterations in DNA repair pathway genes associated with therapy resistance and 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 nonrandomized survival analysis, treatment including both radio- and chemotherapy improved relapse-free and overall survival compared to other treatments in cases with primary grade 3 diagnosis. Similar benefit was not observed for cases with primary grade 2 diagnosis, and radiation as sole postoperative treatment was not significantly improving the prognosis in any of the analyses. CONCLUSION Our results support the previous notions that treatment-induced DNA damage can contribute to tumor progression to grade 4 and suggest that altered DNA repair has a role in treatment resistance and tumor progression.