Mismatch Repair Deficiency in Gliomas: A Rare Insight into Microsatellite Instability and Its Diagnostic Implications

Abstract

Objective

Mismatch repair deficiency (MMRD), a hallmark of microsatellite instability (MSI), has been extensively studied in gastrointestinal and endometrial cancers but remains underexplored in gliomas. Deficiencies in mismatch repair (MMR) proteins, such as MLH1, MSH2, MSH6, and PMS2, may contribute to tumor progression, treatment resistance, and responsiveness to immune checkpoint inhibitors. This study aimed to evaluate the expression of MMR proteins in gliomas using immunohistochemistry (IHC) and analyze their association with patient age, histological subtype, and central nervous system (CNS) World Health Organization (WHO) (2021) tumor grade.

Materials and Methods

A total of 64 glioma cases were retrospectively analyzed, including a range of histologic subtypes and grades. IHC for MLH1, MSH2, MSH6, and PMS2 was performed to detect MMR protein expression. Cases showing MMR deficiency by IHC were further evaluated using next-generation sequencing (NGS) for MSI and frameshift mutations in MMR genes. Statistical analyses were conducted to assess associations with clinicopathological parameters.

Analysis

Quantitative variables were expressed as mean and standard deviation. Quantitative variables were expressed as percentage or proportion. Chi-square test and Fisher's exact test were done to associate MMR protein deficiency with age, histopathological type, and CNS WHO grade of glioma. p-Value of <0.05 was considered significant.

Results

MMR deficiency was observed in 3 of 64 cases (4.69%), all showing isolated loss of MSH6 expression. These included two IDH-mutant astrocytomas and one pilocytic astrocytoma. No significant associations were found between MMRD and age (p = 1.000), histological subtype (p = 0.448), or WHO grade (p = 0.448). NGS revealed one MSI-high and one MSI-low tumor, both harboring frameshift mutations in multiple MMR genes.

Conclusion

MMR deficiency is rare in gliomas, with isolated MSH6 loss being the most common finding. While not significantly associated with tumor grade or patient demographics, MMRD may have clinical relevance in specific subgroups. NGS findings highlight the potential utility of integrating molecular diagnostics for identifying MSI and guiding immunotherapy decisions.

Keywords

mismatch repair protein - microsatellite instability - glioma - immunohistochemistry - astrocytoma

Ethical Approval

The study was performed after ethical approval from Institutional Ethics Committee (IEC/VMMC/SJH/Thesis/06/2022/CC-227).

Patients' Consent

Informed patient consent was taken.

Publication History

Article published online:
09 September 2025

• References

• 1 Jokonya L, Musara A, Esene I. et al. Landscape, presentation, and characteristics of brain gliomas in Zimbabwe. Asian J Neurosurg 2021; 16 (02) 294-299
• 2 Ostrom QT, Patil N, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS. Corrigendum to: CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2013–2017. Neuro-oncol 2022; 24 (07) 1214
• 3 Soldatelli JS, Oliveira IMDE, Kneubil MC, Henriques JAP. Gliomas molecular markers: importance in treatment, prognosis and applicability in brazilian health system. An Acad Bras Cienc 2022; 94 (03) e20211075
• 4 Guarnaccia M, Guarnaccia L, La Cognata V. et al. A targeted next-generation sequencing panel to genotype gliomas. Life (Basel) 2022; 12 (07) 956
• 5 Caccese M, Ius T, Simonelli M. et al. Mismatch- repair protein expression in high-grade gliomas: a large retrospective multicenter study. Int J Mol Sci 2020; 21 (18) 6716
• 6 Alphones S, Chatterjee U, Singh A. et al. Immunohistochemical screening for mismatch repair protein deficiency in paediatric high-grade gliomas - institutional experience and review of literature. Childs Nerv Syst 2021; 37 (08) 2521-2530
• 7 Baretti M, Le DT. DNA mismatch repair in cancer. Pharmacol Ther 2018; 189: 45-62
• 8 Mestrallet G, Brown M, Bozkus CC, Bhardwaj N. Immune escape and resistance to immunotherapy in mismatch repair deficient tumors. Front Immunol 2023; 14: 1210164
• 9 Viana-Pereira M, Lee A, Popov S. et al. Microsatellite instability in pediatric high grade glioma is associated with genomic profile and differential target gene inactivation. PLoS One 2011; 6 (05) e20588
• 10 Alvino E, Fernandez E, Pallini R. Microsatellite instability in primary brain tumors. Neurol Res 2000; 22 (06) 571-575
• 11 Dedeurwaerdere F, Claes KB, Van Dorpe J. et al. Comparison of microsatellite instability detection by immunohistochemistry and molecular techniques in colorectal and endometrial cancer. Sci Rep 2021; 11 (01) 12880
• 12 Tepeoglu M, Borcek P, Ozen O, Altinors N. Microsatellite instability in glioblastoma: is it really relevant in tumor prognosis?. Turk Neurosurg 2019; 29 (05) 778-784
• 13 Galuppini F, Opocher E, Tabori U. et al. Concomitant IDH wild-type glioblastoma and IDH1-mutant anaplastic astrocytoma in a patient with constitutional mismatch repair deficiency syndrome. Neuropathol Appl Neurobiol 2018; 44 (02) 233-239
• 14 Weller M, Wick W, Aldape K. et al. Glioma. Nat Rev Dis Primers 2015; 1: 15017
• 15 Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008; 455 (7216): 1061-1068
• 16 Ohgaki H, Kleihues P. The definition of primary and secondary glioblastoma. Clin Cancer Res 2013; 19 (04) 764-772
• 17 Jones C, Karajannis MA, Jones DTW. et al. Pediatric high-grade glioma: biologically and clinically in need of new thinking. Neuro-oncol 2017; 19 (02) 153-161
• 18 Louis DN, Perry A, Wesseling P. et al. The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro-oncol 2021; 23 (08) 1231-1251
• 19 Dumke R, Dumke C, Eberle F. et al. Monocentric evaluation of Ki-67 labeling index in combination with a modified RPA score as a prognostic factor for survival in IDH-wildtype glioblastoma patients treated with radiochemotherapy. Strahlenther Onkol 2022; 198 (10) 892-906
• 20 McCord M, Steffens A, Javier R, Kam K-L, McCortney K, Horbinski C. The efficacy of DNA mismatch repair enzyme immunohistochemistry as a screening test for hypermutated gliomas. Acta Neuropathol Commun 2020; 8 (01) 15
• 21 Amayiri N, Tabori U, Campbell B. et al; BMMRD Consortium. High frequency of mismatch repair deficiency among pediatric high grade gliomas in Jordan. Int J Cancer 2016; 138 (02) 380-385
• 22 Carrato C, Sanz C, Muñoz-Mármol AM. et al. The challenge of diagnosing constitutional mismatch repair deficiency syndrome in brain malignancies from young individuals. Int J Mol Sci 2021; 22 (09) 4629
• 23 Almuhaisen G, Alhalaseh Y, Mansour R, Abu-Shanab A, Al-Ghnimat S, Al-Hussaini M. Frequency of mismatch repair protein deficiency and PD-L1 in high-grade gliomas in adolescents and young adults (AYA). Brain Tumor Pathol 2021; 38 (01) 14-22
• 24 Vladimirova V, Denkhaus D, Soerensen N, Wagner S, Wolff JEA, Pietsch T. Low level of microsatellite instability in paediatric malignant astrocytomas. Neuropathol Appl Neurobiol 2008; 34 (05) 547-554
• 25 Suwala AK, Stichel D, Schrimpf D. et al. Primary mismatch repair deficient IDH-mutant astrocytoma (PMMRDIA) is a distinct type with a poor prognosis. Acta Neuropathol 2021; 141 (01) 85-100
• 26 Yip S, Miao J, Cahill DP. et al. MSH6 mutations arise in glioblastomas during temozolomide therapy and mediate temozolomide resistance. Clin Cancer Res 2009; 15 (14) 4622-4629
• 27 Cahill DP, Levine KK, Betensky RA. et al. Loss of the mismatch repair protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment. Clin Cancer Res 2007; 13 (07) 2038-2045
• 28 Hunter C, Smith R, Cahill DP. et al. A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Cancer Res 2006; 66 (08) 3987-3991
• 29 van der Werf-'t Lam AS, Terlouw D, Tops CM. et al. Discordant staining patterns and microsatellite results in tumors of MSH6 pathogenic variant carriers. Mod Pathol 2023; 36 (09) 100240
• 30 Vilar E, Gruber SB. Microsatellite instability in colorectal cancer-the stable evidence Nat Rev Clin Oncol 2010; 7 (03) 153-162
• 31 Haynes T, Gilbert MR, Breen K, Yang C. Pathways to hypermutation in high-grade gliomas: mechanisms, syndromes, and opportunities for immunotherapy. Neurooncol Adv 2024; 6 (01) vdae105
• 32 Johnson BE, Mazor T, Hong C. et al. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science 2014; 343 (6167): 189-193
• 33 Touat M, Li YY, Boynton AN. et al. Mechanisms and therapeutic implications of hypermutation in gliomas. Nature 2020; 580 (7804): 517-523
• 34 Le DT, Uram JN, Wang H. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015; 372 (26) 2509-2520
• 35 Marcus L, Fashoyin-Aje LA, Donoghue M. et al. FDA approval summary: pembrolizumab for the treatment of tumor mutational burden-high solid tumors. Clin Cancer Res 2021; 27 (17) 4685-4689
• 36 Zhao J, Chen AX, Gartrell RD. et al. Immune and genomic correlates of response to anti-PD-1 therapy in glioblastoma. Nat Med 2019; 25 (06) 1022
• 37 Bouffet E, Larouche V, Campbell BB. et al. Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. J Clin Oncol 2016; 34 (19) 2206-2211
• 38 Campbell BB, Light N, Fabrizio D. et al. Comprehensive analysis of hypermutation in human cancer. Cell 2017; 171 (05) 1042-1056.e10
• 39 Gatalica Z, Snyder C, Maney T. et al. Programmed cell death 1 (PD-1) and its ligand (PD-L1) in common cancers and their correlation with molecular cancer type. Cancer Epidemiol Biomarkers Prev 2014; 23 (12) 2965-2970