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This study aims to characterize the prevalence and molecular features of gliomas associated with Lynch syndrome mutations.

April 17, 2026Open Access

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

Key Points

This study aims to characterize the prevalence and molecular features of gliomas associated with Lynch syndrome mutations.
Retrospective analysis of 5,594 glioma patients
Targeted next-generation sequencing to identify germline mutations
Comparison of clinical and molecular characteristics between LS glioma and LS colorectal cancer patients
Evaluation of treatment responses to temozolomide
54 glioma patients (0.97%) were identified with pathogenic Lynch syndrome mutations
68.5% of these cases were high-grade gliomas
Distinct mutation patterns observed in MSH2 and MSH6 compared to colorectal cancer
Lower frequencies of tumor mutational burden and microsatellite instability in glioma patients
LS glioma patients generally responded well to temozolomide, but those with MSH2 mutations had a worse prognosis

Abstract

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. 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. 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. 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. Our study identifies 54 LS-associated glioma patients, with distinct molecular and clinical features compared to Lynch CRC patients, and a generally favorable response to temozolomide, though MSH2 mutations are linked to poorer prognosis.

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