Giant cell glioblastoma is a rare subtype of glioblastoma characterized by the presence of numerous large and morphologically bizarre tumor cells. Clinically, giant cell glioblastoma tends to have a better prognosis compared to classic glioblastoma. The genomic profile of giant cell glioblastoma differs from that of classic glioblastoma, which likely contributes to its distinct clinical behavior. While classic glioblastoma commonly exhibits a combination of TERT mutation, EGFR amplification, CDKN2A/B loss, and +7/−10 chromosome copy-number alterations, giant cell glioblastoma often shows TP53 and PTEN mutations, with TP53 mutation being the most frequently observed alteration, present in 90% of cases. Recently, a subgroup of giant cell glioblastoma with a near-haploid genome has been identified (4).

Germline mutations in several DNA repair-related genes, including TP53, POLE, and DNA mismatch repair genes MSH1 and MLH2 (1–3), have been associated with giant cell glioblastoma, indicating the significance of DNA repair deficiency in the development of this tumor subtype. Here, we present a case involving a germline mutation in the CHEK2 gene, which is also involved in the DNA damage response pathway. CHEK2 is part of the ATM-CHEK2-p53 axis, which plays a crucial role in the cellular response to DNA damage. Upon detection of DNA damage by ATM, CHEK2 is activated and phosphorylates p53, leading to cell cycle arrest for DNA repair or apoptosis to prevent malignant transformation.

Germline mutations in TP53 are associated with Li-Fraumeni syndrome, characterized by an increased risk of various cancers, including brain tumors, breast cancer, leukemia, sarcoma, adrenocortical carcinoma, and colon cancer (5). Some individuals with Li-Fraumeni syndrome do not have TP53 mutations but harbor other mutations, including CHEK2 mutations. In our patient, who has giant cell glioblastoma, the CHEK2 mutation was inherited from their father, who had gastric cancer and renal cell carcinoma. The CHEK2 p.H371Y mutation, located in the kinase domain, results in reduced kinase activity in functional assays [PMID: 21618645] and is associated with breast cancer [PMID: 24390236]. Additionally, breast cancer patients carrying the CHEK2 p.H371Y mutation are more likely to respond to neoadjuvant chemotherapy compared to non-carriers [PMID: 25884806]. To the best of our knowledge, this is the first documented case of a germline CHEK2 mutation in giant cell glioblastoma, thereby providing additional evidence for the importance of compromised DNA repair mechanisms in the development of this disease.

A 53-year-old male presented with symptoms of delirium, abnormal behavior, and unresponsiveness. Magnetic Resonance Imaging (MRI) revealed a 75 x 50 mm irregular abnormal signal in the left temporal lobe. T1-weighted images showed hypo-to-isointense signals, while T2-weighted images displayed heterogeneous hyperintense signals. Diffusion-weighted imaging (DWI) indicated diffuse restriction, with surrounding edema and ring enhancement ( Figures 1A–D ). These radiological findings were suggestive of glioblastoma. A surgical procedure successfully removed a tumor measuring 50 x 60 x 70 mm. Histopathological analysis of the FFPE tumor tissue section revealed the presence of pleomorphic cells with numerous bizarre multinucleated giant cells and frequent mitotic figures. Immunohistochemical staining showed positive results for GFAP, Olig-2, MGMT, MAP2, ATRX, P53, EGFR, S100, focal vimentin and negative for IDH-1, NeuN, H3K27M, Syn, and CD34. Ki-67 staining demonstrated a high proliferation index of 60% ( Figures 1E–H ; Supplementary Figure 1 ). Based on these findings, a diagnosis of giant cell glioblastoma was made.

Targeted DNA NGS of 638 cancer genes coupled with whole-genome single-nucleotide polymorphism (SNP) analysis was performed on tumor DNA. The results revealed a near-haploid genome with widespread loss of heterozygosity throughout the genome, except for chromosomes 7 and 18, which maintained heterozygosity. Notably, both copies of chromosome 13 were lost ( Figure 2A ). Additionally, three mutations were detected: TP53 p.T125K, PTEN p.D52M fs*2, and CHEK2 p.H371Y. While the TP53 and PTEN mutations were identified as somatic mutations, the CHEK2 mutation was also observed in the patient’s peripheral blood specimen, confirming a germline CHEK2 mutation.

The patient’s family history revealed that the patient’s father had a history of gastric cancer and renal cell carcinoma, both diagnosed at the age of 72. Subsequent CHEK2 mutation screening in the family confirmed that the patient’s father carried the same CHEK2 mutation. Additionally, the patient’s sister and son were found to carry the same CHEK2 mutation, although they have not reported any tumors at the ages of 57 and 31, respectively ( Figure 2B ).

Further analysis was conducted using targeted RNA NGS on a fresh tumor sample, which identified a PTPRZ1-MET rearrangement. Specifically, exon 2 of PTPRZ1 was fused with exon 2 of MET, resulting in a chimeric protein with an intact reading frame ( Figure 3A ). The chimeric protein retained a partial alpha-carbonic anhydrase domain from PTPRZ1 and all functional domains from MET, similar to previously described rearrangements (6). The PTPRZ1-MET fusion was confirmed an RT-PCR assay using primers specific to PTPRZ1 and MET followed by Sanger sequencing ( Figures 3B, C ). Methylation-specific PCR (MSP) and capillary electrophoresis were performed by evaluating MGMT promoter CpG methylation. The results of this analysis demonstrated methylated MGMT status ( Supplementary Figure 2 ).

Two cycles of temozolomide (TMZ) therapy and one cycle of external beam radiation therapy (EBRT) were administered. Unfortunately, the patient did not respond to these treatments and succumbed to the disease 10 months after the initial diagnosis.

The presence of numerous giant cells is considered a classification-defining feature for giant cell glioblastoma. Giant cells can be seen in various physiological and pathological conditions. The multinucleated osteoblasts, macrophages, and muscle cells are formed by cell fusion. The hepatocytes and trophoblasts during placental development are cells of endoduplication, i.e., cells with repeated rounds of DNA replication without subsequent cell division. Giant cells can be observed in various types of tumors. Alongside giant cell glioblastoma, they are also commonly found in other tumors including bone tumors such as giant cell tumor of bone, chondroblastoma, and aneurysmal bone cyst (7–9). Additionally, giant cells can be present in soft tissue tumors such as dedifferentiated liposarcoma and undifferentiated pleomorphic sarcoma (10, 11). Furthermore, the Hodgkin and Reed-Sternberg cells are a characteristic feature of Hodgkin’s lymphoma (12). The mechanisms underlying giant cell formation in malignancies are likely disease-specific. In the case of giant cell glioblastoma, DNA repair deficiency and genome instability may play a role. DNA repair mechanisms are tightly linked to cell cycle checkpoints, which ensure proper DNA replication and repair prior to cell division. If these checkpoints fail due to DNA repair deficiencies, cells with damaged DNA can proceed through the cell cycle and divide, resulting in abnormal chromosome numbers, including polyploidy. Additionally, DNA repair defects can disrupt the normal process of cytokinesis, the division of replicated genetic material into two daughter cells. Failed cytokinesis can lead to polyploidy. DNA repair defects also promote the occurrence of breakage-fusion-bridge (BFB), a mechanism that accumulates chromosome aberrations through consecutive cell divisions, however, giant cell glioblastoma generally does not exhibit intrachromosomal gains or losses (13). Therefore, the BFB mechanism is not likely to be involved in the formation of giant polyploid cells in giant cell glioblastoma.

Giant cell glioblastoma commonly exhibits two genomic changes: TP53 mutation and a haploid genome. Interestingly, a subset of B-cell acute lymphoblastic leukemia (B-ALL) patients with a near-haploid genome also carries a germline TP53 mutation (14). The concurrent occurrence of TP53 mutation and haploid genome in both giant cell glioblastoma and B-ALL suggests a potential causative association. The haploid genome in cancer cells is thought to result from mitotic catastrophe, leading to the simultaneous loss of multiple suppressor genes, which can drive cancer cell evolution efficiently. However, such a dramatic genomic alteration would typically trigger apoptosis. P53 is a key regulator of cell death in response to genome instability, and its loss of function may help cancer cells evade cell death, even in the presence of mitotic catastrophe (15), thereby facilitating further malignant evolution.

The PTPRZ1-MET fusion has been identified in several types of cancer, mostly in glioblastoma and lung cancer (16, 17). The chimeric PTPRZ1-MET protein functions as a constitutively activated tyrosine kinase involved in processes such as cell proliferation, survival, and migration (18). MET-specific inhibitors, such as Tepotinib and Capmatinib, have been FDA-approved for the treatment of metastatic non-small cell lung cancer (NSCLC) with MET exon 14 skipping activation mutations. These inhibitors have shown efficacy in vitro against glioblastoma with PTPRZ1-MET rearrangement; however, their clinical efficacy in glioblastoma is currently unclear, with ongoing clinical trials investigating their potential.

In conclusion, we present a rare case of giant cell glioblastoma with an inherited germline CHEK2 mutation. Both CHEK2 and p53 are integral components of the ATM-CHEK2-p53 axis, and the simultaneous occurrence of a germline CHEK2 mutation and somatic TP53 mutation in this case strongly suggests the involvement of DNA repair deficiency in the development of this disease.