Abstract
Glioblastoma (GBM) is a relatively rare manifestation of Lynch syndrome (LS), and its defining characteristics are not yet fully defined. This study employs an integrated analysis of the clinicopathological, molecular, and tumor immune microenvironment features of LS-GBMs to elucidate its distinct biology and inform diagnostic and therapeutic strategies. We collected GBM samples from 29 LS patients across multiple medical centers. Germline MMR gene testing confirmed the following mutations among the 29 LS-GBM cases: MSH2 (16 cases, 55.2%), MLH1 (6 cases, 20.7%), MSH6 (4 cases, 13.8%), and PMS2 (1 case, 3.4%). Two cases (6.9%) exhibited no detectable pathogenic germline variants. Patients presented at a mean age of 45.7 years (range 10–69), significantly younger than those with IDH-mutant astrocytoma (WHO grade 4) (P < 0.05) or conventional IDH-wildtype GBMs (IDH-wt cGBMs; P < 0.001). Notably, IDH-wt LS-GBMs demonstrated superior overall survival compared to IDH-wt cGBMs (P < 0.05). Histopathologically, 96.6% (28/29) of cases displayed multinucleated giant cells, with 89.7% (26/29) exhibiting a wreath-like nuclear pattern. Additionally, 58.6% (17/28) demonstrated areas with oligodendroglioma-like characteristics. Molecular profiling revealed high-frequency mutations in TP53 (82.8%, 24/29) and SETD2 (53.6%, 15/28), suggesting concomitant dysregulation of cell cycle control and chromatin remodeling pathways. Furthermore, frequent pathogenic mutations were observed in NF1 (64.3%, 18/28), along with activating mutations in PDGFRA (39.3%, 11/28) and EGFR (32.1%, 9/29), suggesting tumor proliferation and invasion driven by receptor tyrosine kinase (RTK) signaling, such as the Ras/MAPK pathway. Moreover, the MMR-deficient state results in a high tumor mutational burden (100%, 16/16, ≥ 10 muts/Mb) and an inflamed tumor microenvironment with abundant CD8+ T-cell and CD163+ macrophages infiltration. Our findings establish LS-GBMs as a distinct molecular subtype of GBM, driven by convergent defects in DNA repair, cell cycle regulation, and RTK signaling, and highlighted by an immunogenic microenvironment. An integrated diagnostic approach is crucial for its identification, and tailored therapeutic strategies, including immune checkpoint inhibitors and targeted agents, should be explored. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-026-02246-6.