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

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.