Mismatch repair–deficient glioma with spatially distinct IDH-mutant and IDH-wild type components arising in the setting of Lynch syndrome

Sep 24, 2026

Pathogenic mutations in MLH1, MSH2, PMS2, and MSH6 disrupt DNA mismatch repair and, in the heterozygous state, cause Lynch syndrome with predisposition to multiple cancers. Rarely, germline alterations in these genes contribute to primary central nervous system tumors. This report describes an adult woman without prior cancer who presented with multicentric, infiltrative supratentorial glioma. Spatially distinct lesions showed discordant IDH status and histologic grade, yet both contained an MLH1 frameshift variant identified in germline testing, supporting monoallelic germline mismatch repair deficiency as the underlying cause.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages8

Reading Time20 min

AccessFree to download

Case presentation

Imaging findings

Surgical treatment

Histopathology and molecular evaluation

C O L D S P R I N G H A R B O R Molecular Case Studies RAPID COMMUNICATION Corresponding author: [woodmat@ohsu.edu](woodmat@ohsu.edu) | © 2023 Tan et al. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License, which permits reuse andredistribution, except for commercial purposes, provided that the original author and source are credited. | | --- | | Ontology term: neoplasm of the central nervous system | Published by Cold Spring Harbor Laboratory Press doi:10.1101/mcs.a006280 Mismatch repair–deficient glioma with spatially distinct IDH-mutant and IDH-wild type components arising in the setting of Lynch syndrome Hao Tan,1 Caleb Nerison,1 Cooper Stateler,1 Stephen G. Bowden,1 Ahmed M. Raslan,1 Prakash Ambady,2 Ramon F. Barajas, Jr.,3,4,5 and Matthew D. Wood5,6 1Department of Neurological Surgery, Oregon Health & Science University, Portland, Oregon 97239, USA; 2Providence Neurological Specialties-West, Portland, Oregon 97225, USA; 3Department of Diagnostic Radiology, 4Advanced Imaging Research Center, 5Knight Cancer Institute, 6Department of Pathology and Laboratory Medicine, Oregon Health & Science University, Portland, Oregon 97239, USA Abstract Pathogenic mutations in MLH1, MSH2, PMS2, and MSH6 compromise DNA mismatch repair mechanisms and in the heterozygous state result in Lynch syndrome, which is typified by a predisposition to endometrial, ovarian, colorectal, gastric, breast, hematologic, and soft tissue cancers. Rarely, germline pathogenic aberrations in these genes are associated with the development of primary central nervous system tumors. We present a report of an adult female with no prior cancer history who presented with a multicentric, infiltrative supratentorial glioma involving both the left anterior temporal horn and left precentral gyrus. Surgical treatment and neuropathological/molecular evaluation of these lesions revealed discordant isocitrate dehydrogenase (IDH) status and histologic grade at these spatially distinct disease sites. A frameshift alteration within the MLH1 gene (p.R217fs∗ 12, c.648delT) was identified in both lesions and subsequently identified in germline testing of a blood sample, consistent with Lynch syndrome. Despite distinct histopathologic features and divergent IDH status of the patient’s tumors, the molecular findings suggest that both sites of intracranial neoplasia may have developed as a consequence of underlying monoallelic germline mismatch repair deficiency. This case illustrates the importance of characterizing the genetic profile of multicentric gliomas and highlights the oncogenic potential of germline mismatch repair gene pathogenic alterations within central nervous system gliomas. [Supplemental material is available for this article.] CASE PRESENTATION A 36-yr-old female with a history of cortical venous sinus thrombosis presented to our institution complaining of worsening headaches and seizures. Brain imaging obtained on admission revealed noncontiguous, T2/FLAIR hyperintense, non–contrast enhancing lesions involving the left temporal pole and left precentral gyrus. These findings raised concern for a multicentric low-grade infiltrating glioma. Though surgery was recommended, the patient opted to not pursue surgery at the time and was discharged with a plan for further follow-up. She was readmitted 1 month later for recurrent seizures, with radiographic evidence Cite this article as Tan et al. 2023 Cold Spring Harb Mol Case Stud 9: a006280 1 of 8 C O L D S P R I N G H A R B O R Molecular Case Studies Multicentric glioma in Lynch syndrome of disease progression and clinical concern for elevated intracranial pressure and local mass effect. She underwent an emergent, left-sided decompressive frontotemporal craniectomy and resection of her left anterior temporal pole (Fig. 1A) . This was followed 2 wk later by aredo frontotemporal craniotomy for resection of the frontal tumor involving the

FAQs

What genetic mechanism links Lynch syndrome to the patient’s glioma?

The case identifies a frameshift alteration in the MLH1 gene (p.R217fs∗ 12, c.648delT). The same variant is found in germline testing, consistent with Lynch syndrome and underlying monoallelic mismatch repair deficiency.

How did the two spatially distinct tumor sites differ clinically and pathologically?

The lesions were multicentric and infiltrative but showed discordant isocitrate dehydrogenase (IDH) status and different World Health Organization (WHO) grades.

What were the key molecular and immunohistochemical findings supporting shared and distinct tumor features?

Both sites shared pathogenic alterations in ATRX and TP53, while one temporal lesion showed IDH1 mutant protein immunoreactivity (p.R132H) and the frontal lesion lacked IDH1 p.R132H staining and had excluded IDH1/IDH2 mutations by NGS.

Sep 24, 2026

Uploaded by Valentina