Diagnostic and therapeutic challenges of glioblastoma as an initial malignancy of constitutional mismatch repair deficiency (CMMRD): two case reports and a literature review

Onishi, Shumpei; Yamasaki, Fumiyuki; Kuraoka, Kazuya; Taguchi, Akira; Takayasu, Takeshi; Akagi, Kiwamu; Hinoi, Takao

doi:10.1186/s12920-022-01403-9

Cited by 4 publications

(2 citation statements)

References 23 publications

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“…Mutation, deletion, or promoter methylation of these MMR genes is present in approximately 12% of ovarian cancers, 15% of colorectal cancer, 22% of gastric cancers, and up to 30% of endometrial cancers, as well as heritable cancer syndromes, such as Lynch syndrome (monoallelic germline mutation of an MMR gene) and constitutional mismatch repair deficiency (CMMRD; biallelic germline mutation of an MMR gene), which have an increased risk of numerous cancers [ 40 , 84 , 105 , 106 ]. In diffusely infiltrating gliomas, mutations in MMR genes may occur as part of a germline syndrome [ 28 , 59 , 75 , 84 , 105 , 106 , 161 , 200 ], as sporadic mutations [ 27 , 32 , 179 , 209 ], or as the result of temozolomide therapy, either due to the selection of temozolomide-resistant MMR-deficient clones or by temozolomide-induced mutation in one of the MMR genes [ 6 , 17 , 31 , 45 , 53 , 94 , 104 , 179 , 209 , 213 , 233 ].…”

Section: Mismatch Repair (Mmr) Protein Defects and Microsatellite Ins...mentioning

confidence: 99%

Genetic and epigenetic instability as an underlying driver of progression and aggressive behavior in IDH-mutant astrocytoma

Richardson,

Walker,

Hambardzumyan

et al. 2024

Acta Neuropathol

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In recent years, the classification of adult-type diffuse gliomas has undergone a revolution, wherein specific molecular features now represent defining diagnostic criteria of IDH-wild-type glioblastomas, IDH-mutant astrocytomas, and IDH-mutant 1p/19q-codeleted oligodendrogliomas. With the introduction of the 2021 WHO CNS classification, additional molecular alterations are now integrated into the grading of these tumors, given equal weight to traditional histologic features. However, there remains a great deal of heterogeneity in patient outcome even within these established tumor subclassifications that is unexplained by currently codified molecular alterations, particularly in the IDH-mutant astrocytoma category. There is also significant intercellular genetic and epigenetic heterogeneity and plasticity with resulting phenotypic heterogeneity, making these tumors remarkably adaptable and robust, and presenting a significant barrier to the design of effective therapeutics. Herein, we review the mechanisms and consequences of genetic and epigenetic instability, including chromosomal instability (CIN), microsatellite instability (MSI)/mismatch repair (MMR) deficits, and epigenetic instability, in the underlying biology, tumorigenesis, and progression of IDH-mutant astrocytomas. We also discuss the contribution of recent high-resolution transcriptomics studies toward defining tumor heterogeneity with single-cell resolution. While intratumoral heterogeneity is a well-known feature of diffuse gliomas, the contribution of these various processes has only recently been considered as a potential driver of tumor aggressiveness. CIN has an independent, adverse effect on patient survival, similar to the effect of histologic grade and homozygous CDKN2A deletion, while MMR mutation is only associated with poor overall survival in univariate analysis but is highly correlated with higher histologic/molecular grade and other aggressive features. These forms of genomic instability, which may significantly affect the natural progression of these tumors, response to therapy, and ultimately clinical outcome for patients, are potentially measurable features which could aid in diagnosis, grading, prognosis, and development of personalized therapeutics.

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Section: Mismatch Repair (Mmr) Protein Defects and Microsatellite Ins...mentioning

confidence: 99%

Genetic and epigenetic instability as an underlying driver of progression and aggressive behavior in IDH-mutant astrocytoma

Richardson,

Walker,

Hambardzumyan

et al. 2024

Acta Neuropathol

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“… 20 Subsequently, other examples of both sporadic and inherited MMR-mutation-associated gliomas and other brain tumors have been identified. 21 , 22 …”

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confidence: 99%

Mismatch repair protein mutations in isocitrate dehydrogenase (IDH)-mutant astrocytoma and IDH-wild-type glioblastoma

Richardson

Yokoda

Rashidipour

et al. 2023

Neuro-Oncology Advances

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Background Mutations in mismatch repair (MMR) genes (MSH2, MSH6, MLH1, and PMS2) are associated with microsatellite instability and a hypermutator phenotype in numerous systemic cancers, and germline MMR mutations have been implicated in multi-organ tumor syndromes. In gliomas, MMR mutations can function as an adaptive response to alkylating chemotherapy, although there are well documented cases of germline and sporadic mutations, with detrimental effects on patient survival. Methods The clinical, pathologic, and molecular features of 18 IDH-mutant astrocytomas and 20 IDH-wildtype glioblastomas with MMR mutations in the primary tumor were analyzed in comparison to 361 IDH-mutant and 906 IDH-wildtype tumors without MMR mutations. In addition, 12 IDH-mutant astrocytomas and 18 IDH-wildtype glioblastomas which developed MMR mutations between initial presentation and tumor recurrence were analyzed in comparison to 50 IDH-mutant and 104 IDH-wildtype cases that remained MMR-wildtype at recurrence. Results In both IDH-mutant astrocytoma and IDH-wildtype glioblastoma cohorts, the presence of MMR mutation in primary tumors was associated with significantly higher tumor mutation burden (TMB) (p<0.0001), however MMR mutations only resulted in worse overall survival in the IDH-mutant astrocytomas (p=0.0069). In addition, gain of MMR mutation between the primary and recurrent surgical specimen occurred more frequently with temozolomide therapy (p=0.0073), and resulted in a substantial increase in TMB (p<0.0001), higher grade (p=0.0119), and worse post-recurrence survival (p=0.0022) in the IDH-mutant astrocytoma cohort. Conclusions These results suggest that whether present initially or in response to therapy, MMR mutations significantly affect TMB but appear to only influence the clinical outcome in IDH-mutant astrocytoma subsets.

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A new application of fractional derivatives for predicting human glioblastoma multiforme tumor growth

Hosseininia,

Bavi,

Heydari

et al. 2024

Engineering Analysis with Boundary Elements

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Diagnostic and therapeutic challenges of glioblastoma as an initial malignancy of constitutional mismatch repair deficiency (CMMRD): two case reports and a literature review

Cited by 4 publications

References 23 publications

Genetic and epigenetic instability as an underlying driver of progression and aggressive behavior in IDH-mutant astrocytoma

Genetic and epigenetic instability as an underlying driver of progression and aggressive behavior in IDH-mutant astrocytoma

Mismatch repair protein mutations in isocitrate dehydrogenase (IDH)-mutant astrocytoma and IDH-wild-type glioblastoma

A new application of fractional derivatives for predicting human glioblastoma multiforme tumor growth

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