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. 2025 May 28:2025:4321571.
doi: 10.1155/humu/4321571. eCollection 2025.

A Novel Germline MUTYH Mutation (p.W156∗) in High-Grade Astrocytoma, IDH Mutant

Lulu Zhang  1   2 , Shaoyan Xi  1   3 , Lei Yuan  1   3 , Ziteng Li  1   3 , Xiaoyun Liu  1   2 , Jiamei Gu  1   2 , Shuo Li  1   3 , Liyun Huang  1   3 , Wanming Hu  1   3 , Lingyi Fu  1   3
Affiliations

A Novel Germline MUTYH Mutation (p.W156∗) in High-Grade Astrocytoma, IDH Mutant

Lulu Zhang et al. Hum Mutat. .

Abstract

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.

Keywords: IDH; MET; MUTYH; astrocytoma; germline mutation.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Clinical and histopathological characteristics of Case 1. (a) MRI revealed the lesion in the left frontal lobe. (b) The morphology of high-grade diffuse glioma (100×). (c) Hypercellularity and increased proliferative activity (200×). (d) Immunoreactivity for GFAP (100×). (e) Immunoreactivity for Olig2 (100×). (f) Strong and diffuse positive staining for IDH1 R132H (100×). (g) The expression of ATRX was absent (100×). (h) The Ki-67 labeling index was about 8% (100×).
Figure 2
Figure 2
Clinical and histopathological characteristics of Case 2. (a) MRI revealed the lesion in the right frontal lobe. (b) The morphology of giant cell glioblastoma (100×). (c) Patchy tumoral necrosis (100×). (d) Immunoreactivity for GFAP (100×). (e) Immunoreactivity for Olig2 (100×). (f) IDH1 R132H was negative (100×). (g) The expression of ATRX was retained (100×). (h) Strong and diffuse positive staining for P53 (100×). (i) The Ki-67 labeling index was about 40% (100×).
Figure 3
Figure 3
Gene expression profiling. (a) Chromosomal CNVs. (b) Amplification of the MET gene. (c) Schematic diagram of MUTYH variants. (d) Methylation of the MGMT promoter in Case 2.
Figure 4
Figure 4
Immune microenvironment. (a) Representative HE and IHC images of Case 1. (b) Representative HE and IHC images of Case 2. (c) Representative HE and IHC images of the case with LS.
Figure 5
Figure 5
Survival analysis. (a) Age and gender distribution of the patients. (b) Tumor locations. (c) Tumor subtypes. (d) Illustration of survival information. (e) Survival curves.
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