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. The online version contains supplementary material available at 10.1186/s40478-026-02246-6.

Cancer predisposition syndromes caused by germline pathogenic variants (GPV) in adult-onset cancer predisposition genes (aoCPG) are those for which there is low risk of cancer in children, with genetic testing and screening for these conditions typically deferred until adulthood. GPV in aoCPG have been identified in pediatric oncology patients, but in these cases the potential contribution of the aoCPG to cancer development is often unknown. We investigated the role GPV in aoCPG may play in childhood cancer development. Results of paired tumor-germline sequencing from pediatric oncology patients enrolled from May 2012 to October 2023 were analyzed for frequency of GPV in aoCPG. Germline testing included analysis of up to 182 cancer predisposition genes. Tumor loss-of-heterozygosity, presence of second somatic pathogenic variant, immunohistochemical stain for protein expression, and/or tumor mutation burden were used to determine possible causation. Of the 954 participants, 42 (4.4%) had GPV in aoCPG. Six (14.3%) of these 42 participants had tumor findings indicating their GPV in an aoCPG likely contributed to cancer development: three patients with Lynch syndrome (two anaplastic astrocytomas, one giant cell glioblastoma) and one each with GPV in ATM (craniopharyngioma and diffuse high-grade glioma), BRIP1 (atypical teratoid rhabdoid tumor), and CHEK2 (mixed germ cell tumor of pineal gland). These findings contribute to the literature suggesting that, rarely, GPV in aoCPG may contribute to cancer diagnoses in children, raising the question of how tumors in these cases may present differently in children than adults. Increased knowledge about potential childhood cancer risks related to what have historically been considered aoCPG could modify predictive genetic testing recommendations for children and enhance existing cancer screening protocols.

Germline mutations in the DNA repair gene E. coli MutY homolog (MUTYH) are established predisposing factors for colorectal polyposis, colorectal carcinoma, and various extracolonic malignancies. Nevertheless, the association between MUTYH mutations and central nervous system (CNS) tumorigenesis remains poorly characterized. In this study, we reported the first identification of a novel c.467G > A (p.W156∗) MUTYH variant in two patients with high-grade astrocytoma, IDH mutant, which was classified as pathogenic. Histopathological evaluation revealed tumor morphologies consistent with either diffuse glioma or giant cell glioblastoma. Comparative analysis with mismatch repair (MMR)-deficient tumors demonstrated that patients carrying MUTYH mutations exhibited microsatellite stability, relatively low tumor mutation burden (TMB), and an immunosuppressive microenvironment, indicating difficulties in benefiting from immunotherapy. Fortunately, gain of Chromosome 7, in association with amplification of the MET gene, was detected, underscoring the possible application of targeted drugs. Integrating previous studies, we summarized germline MUTYH mutations in 11 cases of high-grade neuroepithelial tumors (eight gliomas and three medulloblastomas). This cohort demonstrated a predilection for pediatric and young adult populations without significant gender predominance. Our findings suggested a potential association between germline MUTYH mutations and CNS tumor susceptibility.

Giant cell (gc)-enriched glioblastoma (gcGB) represents a distinct histological variant of isocitrate dehydrogenase wild-type adult-type glioblastoma with notable enlarged mono- or multinuclear tumor cells. While some studies suggest a survival advantage for gcGB patients, the underlying causes remain elusive. GcGBs are associated with TP53 mutations, and gcs were shown to accumulate DNA double-strand breaks and show deficient mitosis, potentially triggering cellular senescence programs. Epigenetic clocks have emerged as valuable tools for assessing tumor-induced age acceleration (DNAMethAgeAcc), which has lately proved itself as prognostic biomarker in glioblastoma. Our study aimed to comprehensively analyze the methylome and key metabolic proteins of gcGBs, hypothesizing that they undergo cellular aging programs compared to non-gcGBs. A total of 310 epigenetically classified GBs, including 26 gcGBs, and nine adults with malignant gliomas allocating to pediatric high-grade glioma molecular subclasses (summarized as "pediatric GB") were included. DNAMethAgeAcc was computed by subtraction of chronological patient ages from DNA methylome-derived age estimations and its increase was associated with better survival within gcGB and non-gcGB. GcGBs were significantly more often allocated to the subgroup with increased DNAMethAgeAcc and demonstrated the highest DNAMethAgeAcc. Hypothetical senescence/aging-induced changes of the tumor microenvironment were addressed by tumor deconvolution, which was able to identify a cluster enriched for tumors with increased DNAMethAgeAcc. Key metabolic protein expression did not differ between gcGB and non-gcGB and tumor with versus without increased DNAMethAgeAcc but for elevated levels of one single mitochondrial marker, anti-mitochondrial protein MT-C02, in gcGBs. With its sped-up epigenetic aging, gcGB presented as the epigenetic oldest GB variant in our cohort. Whereas the correlation between accelerated tumor-intrinsic epigenetic aging and cellular senescence in gcGB stays elusive, fostering epigenetic aging programs in GB might be of interest for future exploration of alternative treatment options in GB patients.