A Novel GermlineMutation (p.W156∗) in High-Grade Astrocytoma,Mutant.

in Human mutation by Lulu Zhang, Shaoyan Xi, Lei Yuan, Ziteng Li, Xiaoyun Liu, Jiamei Gu, Shuo Li, Liyun Huang, Wanming Hu, Lingyi Fu

TLDR

  • A novel pathogenic variant in the DNA repair gene was identified in two patients with high-grade astrocytoma, associated with microsatellite stability, low TMB, and an immunosuppressive microenvironment.
  • The study suggests potential applications of targeted drugs and highlights the need for further research to understand the mechanisms underlying germline mutation and CNS tumor susceptibility.

Abstract

Germline mutations in the DNA repair gene() are established predisposing factors for colorectal polyposis, colorectal carcinoma, and various extracolonic malignancies. Nevertheless, the association betweenmutations 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∗)variant in two patients with high-grade astrocytoma,, 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 carryingmutations 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 thegene, was detected, underscoring the possible application of targeted drugs. Integrating previous studies, we summarized germlinemutations 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 germlinemutations and CNS tumor susceptibility.

Overview

  • Main focus of the study: Investigating the association between germline mutations in the DNA repair gene and central nervous system (CNS) tumorigenesis.
  • Methodology: Identification of novel germline variants in patients with high-grade astrocytoma and comparative analysis with mismatch repair (MMR)-deficient tumors.
  • Primary objective: To identify potential biomarkers for targeted therapies and understand the genetic predisposition to CNS tumor susceptibility.

Comparative Analysis & Findings

  • The study identified a novel pathogenic variant c.467G>A (p.W156*) in two patients with high-grade astrocytoma, which was associated with microsatellite stability, low tumor mutation burden (TMB), and an immunosuppressive microenvironment.
  • Compared to MMR-deficient tumors, patients carrying germline mutations exhibited similar characteristics, suggesting difficulties in benefiting from immunotherapy.
  • Gain of Chromosome 7 and amplification of the gene were detected in patients with germline mutations, suggesting potential applications of targeted drugs.

Implications and Future Directions

  • The study highlights the potential association between germline mutations and CNS tumor susceptibility, particularly in pediatric and young adult populations.
  • Further research is needed to elucidate the mechanisms underlying this association and to investigate potential biomarkers for targeted therapies.
  • Integration of germline mutation analysis with other genetic and epigenetic factors may help refine diagnostic and therapeutic approaches for CNS tumors.
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