Incidence, clinicopathologic, and genetic characteristics of mismatch repair gene-mutated glioblastomas

J Neurooncol. 2021 May;153(1):43-53. doi: 10.1007/s11060-021-03710-0. Epub 2021 Apr 17.


Background: Glioblastoma (GBM) is the most common and malignant gliomas of adults and recur, resulting in death, despite surgery, radiotherapy, and temozolomide-based chemotherapy. There are a few reports on immunotherapy for the mismatch repair (MMR)-deficient GBMs with high tumor mutational burden (TMB). However, the clinicopathological and genetic features of the MMR genes altered in GBMs have not been elucidated yet.

Methods: The authors analyzed targeted next-generation sequencing (NGS) data from 282 (276 primary and 6 recurrent) glioblastomas to evaluate the mutational status of six DNA repair-related genes: MLH1, MSH2, MSH6, PMS2, POLE, and POLD1. Tumors harboring somatic or germline mutations in one or more of these six genes were classified as an MMR gene-altered GBM. The clinicopathologic and molecular characteristics of MMR gene-altered GBMs were compared to those of tumors without MMR gene alterations.

Results: Sixty germline or somatic mutations were identified in 37 cases (35 primary and two recurrent) of GBM. The most frequently mutated genes were MSH6 and POLE. Single nucleotide variants were the most common, followed by frameshift deletions or insertions and approximately 60% of the mutations were germline mutations. Two patients who showed MSH2 (c.2038C > T) and MSH6 (c.1082G > A) mutations had familial colon cancer. The clinical findings were not different between the two groups. However, the presence of MGMT promoter methylation and high tumor mutation burden (TMB) values (> 20) were correlated with MMR gene alterations.

Conclusion: Since MMR-related genes can be found even in primary glioblastoma and are correlated with high TMB and MGMT promoter methylation, MMR genes should be carefully analyzed in NGS study on glioblastomas.

Keywords: DNA mismatch repair gene; Glioblastoma; Next-generation sequencing; Tumor mutation burden.

MeSH terms

  • DNA Mismatch Repair* / genetics
  • Glioblastoma* / epidemiology
  • Glioblastoma* / genetics
  • Humans
  • Incidence
  • MutS Homolog 2 Protein / genetics
  • MutS Homolog 2 Protein / metabolism
  • Neoplasm Recurrence, Local


  • MutS Homolog 2 Protein