Abstract
AbstractMismatch repair-deficient (MMRD) brain tumors are rare among primary brain tumors and can be induced by germline or sporadic mutations. Here, we report 13 MMRD-associated (9 sporadic and 4 Lynch syndrome) primary brain tumors to determine clinicopathological and molecular characteristics and biological behavior. Our 13 MMRD brain tumors included glioblastoma (GBM) IDH-wildtype (n = 9) including 1 gliosarcoma, astrocytoma IDH-mutant WHO grade 4 (n = 2), diffuse midline glioma (DMG) H3 K27M-mutant (n = 1), and pleomorphic xanthoastrocytoma (PXA) (n = 1). Next-generation sequencing using a brain tumor-targeted gene panel, microsatellite instability (MSI) testing, Sanger sequencing for germline MMR gene mutation, immunohistochemistry of MMR proteins, and clinicopathological and survival analysis were performed. There were many accompanying mutations, suggesting a high tumor mutational burden (TMB) in 77%, but TMB was absent in one case of GBM, IDH-wildtype, DMG, and PXA, respectively. MSH2, MLH1, MSH6, and PMS2 mutations were found in 31%, 31%, 31% and 7% of patients, respectively. MSI-high and MSI-low were found in 50% and 8% of these gliomas, respectively and 34% was MSI-stable. All Lynch syndrome-associated GBMs had MSI-high. In addition, 77% (10/13) had histopathologically multinucleated giant cells. The progression-free survival tended to be poorer than the patients with no MMRD gliomas, but the number and follow-up duration of our patients were insufficient to get statistical significance. In the present study, we found that the most common MMRD primary brain tumor was GBM IDH-wildtype. The genetic profile of MMRD GBM was different from that of conventional GBM. MMRD gliomas with TMB and MSI-H may be sensitive to immunotherapy but resistant to temozolomide. Our findings can help develop better treatment options.The authors examined 13 mismatch repair-deficient (MMRD)-associated primary brain tumors to determine molecular characteristics and biological behavior. MMRD occurred after chemotherapy and radiotherapy in two cases. The genetic profile of MMRD glioblastoma was different from that of conventional glioblastoma. Half of the MMRD-gliomas and all Lynch syndrome-associated GBMs were high in microsatellite instability. These tumors had high mutational burdens and tended to have shorter progression-free survival than glioma without MMRD.
Highlights
The DNA mismatch repair (MMR) system is responsible for the prevention of genomic instability in cells and is controlled by MMR genes
Microvascular proliferation was observed in 12 cases (92%), and necrosis was observed in 10 cases (77%)
Among the four mutL homolog 1 (MLH1)-mutant tumors, complete loss of both MLH1 and postmeiotic segregation increased 2 (PMS2) IHC in the tumor cells was present in three cases (Patient #1, 9, and 10), but one case showed complete loss of MLH1 and heterogeneous loss of the partner protein PMS2 (Patient #11)
Summary
The DNA mismatch repair (MMR) system is responsible for the prevention of genomic instability in cells and is controlled by MMR genes Those are mutL homolog 1 (MLH1), encoded at chromosome 3p21.3, mutS homolog 2 (MSH2) at chromosome 2p22–21, mutS homolog 6 (MSH6) at chromosome 2p16 and postmeiotic segregation increased 2 (PMS2) at chromosome 7p22.2. MMR deficiency (MMRD) can be caused by germline or sporadic mutations or promoter methylation of MMR genes, which is associated with microsatellite instability (MSI) and tumor mutational burden (TMB). It contributes to tumorigenesis, poor outcomes, and acquired drug resistance to alkylating agents that mediate the formation of O6 methylguanine-containing mismatches[1,2].
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