Long survival in a TP53 germline-mutant glioblastoma with multi‑omics insights

Abstract

Li-Fraumeni syndrome, caused by germline mutations in TP53 , is associated with a high lifetime risk of various malignancies, including Glioblastoma (GBM). Long-term survival in GBM is extremely rare, and the underlying biological mechanisms remain poorly understood, particularly in the context of hereditary cancer syndromes. Here, we present a 22-year-old female patient diagnosed with IDH-wildtype GBM harboring an unmethylated MGMT promoter. Following gross-total resection, she received standard radiotherapy, ten cycles of adjuvant temozolomide (TMZ), and six cycles of autologous cytokine-induced killer cell immunotherapy, resulting in a 7-year progression-free interval. At recurrence, a second resection was performed, and genetic testing revealed a pathogenic germline TP53 mutation (p.R282W), confirming Li-Fraumeni syndrome. The patient survived an additional two years post-recurrence, achieving a total overall survival exceeding nine years. Whole-exome sequencing of the recurrent tumor demonstrated a tumor mutational burden (TMB) of 10.33 mutations per megabase, biallelic TP53 inactivation, and pathogenic mutations in NF1, PIK3CA, and other genes, while lacking EGFR amplification and TERT promoter mutation. Single-cell RNA sequencing revealed a myeloid-dominated immune microenvironment comprising monocytes (~ 23%) and macrophages (~ 4.7%), with strikingly scarce T lymphocytes (~ 0.6%), indicating profound immunosuppression despite high neoantigen load. This case suggests that prolonged TMZ exposure might shape an elevated TMB tumor rendered ineffective by myeloid-driven immune evasion, while initial immunotherapy may have contributed to long-term disease control. These findings provide mechanistic insights into GBM immune evasion and support myeloid-targeted combination strategies for similar molecular contexts.