P18.51.A UNIQUE GENETIC AND EPIGENETIC ALTERATIONS IN GLIOBLASTOMA VERY LONG-TERM SURVIVORS (VLTS): INSIGHTS FROM TWO CLINICAL CASES

Abstract BACKGROUND Glioblastoma (GBM) 5-year survival (LTS) and a 10-year survival (VLTS) rate are extremely low, reaching 7% and 4.7% respectively (2020 CBTRUS Statistical Report). The biological mechanisms that drive the prolonged clinical outcomes remain significantly understudied. MATERIAL AND METHODS As part of a recent study on LTS (PMID: 38423245), here we detail two out of the 17 VLTS cases, addressed with extensive molecular analyses. RESULTS Patient AR 10-046 was a 31-year-old female with a left fronto-parietal giant cell GBM (gcGBM), treated with surgery, radiotherapy and chemotherapy. After 6 months from the diagnosis, she recurred and underwent tumor exeresis and adjuvant TMZ, maintaining disease stability for a total of 243 months. According to the v12.5 BTC the tumor was assigned to the methylation subclass pedHGG_RTK1a subtype (score >0.99), frequently associated with Lynch syndrome (LS). Indeed, we detected MSH6 mutation in tumor DNA as well as in peripheral lymphocyte. We detected high Tumor Mutational Burden. Interestingly, the Copy Number Variation (CNV) plots showed chromosome 1q gain and chromosome 13 loss with no other typical GBM alterations.Patient AR 10-037 was a 70-year-old male with left temporal lobe GBM treated with surgery, adjuvant radiotherapy and chemotherapy, achieving a survival of 73 months. Histology was classical GBM. The tumor was assigned to the pedHGG_MYCN subclass with a suboptimal score (0.5). At CNV examination, apart from the canonical chromosome 7 gain and chromosome 10q loss, we observed MDM2 gene amplification and possible rearrangements on chromosome 12 and 18 with the typical aspect of a chromothripsis (CT), confirmed by RNASeq analysis. Our case presented CT on chr12 harboring two putative gene fusions: CPSF6::CPM and PTPRR::RAB3IP never reported in the literature. CONCLUSION We described two cases of VLTS patients with peculiar molecular profile, widening the scenario of clinical and molecular variability that can be found in such patients. Further studies are still needed to identify the biological mechanisms causing such prognosis, with a fundamental contribution from molecular analyses, including DNAm profiling, NGS and RNAseq. FUNDING RRC Italian Ministry of Health