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Background <p>Lynch syndrome (LS) is an inherited disorder caused by germline mutations in mismatch repair (MMR) genes or EPCAM deletions and is primarily associated with an increased risk of gastrointestinal and endometrial cancers. However, LS-associated gliomas are rare, and their clinical and molecular characteristics remain poorly defined. The objective of this study was to systematically characterize the prevalence, genetic landscape, molecular features, and clinical outcomes of LS-associated gliomas.</p> Methods <p>We retrospectively analyzed a multicenter cohort of 5,594 glioma patients who underwent targeted next-generation sequencing to identify pathogenic germline mutations in LS-associated genes. Clinical characteristics, molecular features, treatment histories, and outcomes of LS-associated glioma patients were systematically evaluated and compared with those of LS-associated colorectal cancer (CRC) patients.</p> Results <p>Among 5,594 glioma patients, 54 individuals (0.97%) were identified as carrying pathogenic germline LS-associated mutations, with a median age of 37.9 years. High-grade gliomas accounted for 68.5% (37/54) of cases, while 9.3% (5/54) were low-grade gliomas. Mutations in <i>MSH2</i> and <i>MSH6</i> were predominant, showing a distribution distinct from that observed in LS-associated colorectal cancer (CRC). Compared with LS CRC patients, LS-associated glioma patients exhibited significantly lower frequencies of high tumor mutational burden (TMB-H), microsatellite instability–high (MSI-H), and PD-L1 positivity, indicating unique molecular characteristics. Treatment history analysis showed that LS glioma patients generally responded well to temozolomide treatment, although those harboring <i>MSH2</i> mutations had a worse prognosis. A family history of cancer was reported in 16.7% (9/54) of LS glioma patients.</p> Conclusions <p>This study provides a comprehensive characterization of the prevalence, molecular landscape, and clinical outcomes of LS-associated gliomas. The distinct molecular features and prognostic implications identified herein may facilitate improved recognition and inform more personalized management strategies for this rare patient population.</p>

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Molecular and clinical characteristics of glioma patients with germline pathogenic mutations of Lynch syndrome genes: a large-scale multicenter study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月15日

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  • Jiao Feng,
  • Tonghui Ma,
  • Xiang Zhang,
  • Yi Zhang,
  • Zhenyuan Qian,
  • Yuxiang Dai,
  • Zhixian Gao,
  • Rui Zhao,
  • Chengjun Yao,
  • Guhong Du,
  • Naiyuan Shao,
  • Zhen Wu,
  • Nan Ji,
  • Jia Gu,
  • Zhengchuan Liu,
  • Qiong Yang,
  • Xiaochen Sun,
  • Wei Li,
  • Xiaomo Li,
  • Yanxiang Zhang,
  • Zaiyuan Ye,
  • Anchao Yang

摘要

Background

Lynch syndrome (LS) is an inherited disorder caused by germline mutations in mismatch repair (MMR) genes or EPCAM deletions and is primarily associated with an increased risk of gastrointestinal and endometrial cancers. However, LS-associated gliomas are rare, and their clinical and molecular characteristics remain poorly defined. The objective of this study was to systematically characterize the prevalence, genetic landscape, molecular features, and clinical outcomes of LS-associated gliomas.

Methods

We retrospectively analyzed a multicenter cohort of 5,594 glioma patients who underwent targeted next-generation sequencing to identify pathogenic germline mutations in LS-associated genes. Clinical characteristics, molecular features, treatment histories, and outcomes of LS-associated glioma patients were systematically evaluated and compared with those of LS-associated colorectal cancer (CRC) patients.

Results

Among 5,594 glioma patients, 54 individuals (0.97%) were identified as carrying pathogenic germline LS-associated mutations, with a median age of 37.9 years. High-grade gliomas accounted for 68.5% (37/54) of cases, while 9.3% (5/54) were low-grade gliomas. Mutations in MSH2 and MSH6 were predominant, showing a distribution distinct from that observed in LS-associated colorectal cancer (CRC). Compared with LS CRC patients, LS-associated glioma patients exhibited significantly lower frequencies of high tumor mutational burden (TMB-H), microsatellite instability–high (MSI-H), and PD-L1 positivity, indicating unique molecular characteristics. Treatment history analysis showed that LS glioma patients generally responded well to temozolomide treatment, although those harboring MSH2 mutations had a worse prognosis. A family history of cancer was reported in 16.7% (9/54) of LS glioma patients.

Conclusions

This study provides a comprehensive characterization of the prevalence, molecular landscape, and clinical outcomes of LS-associated gliomas. The distinct molecular features and prognostic implications identified herein may facilitate improved recognition and inform more personalized management strategies for this rare patient population.