Temozolomide Induced Hypermutation in Glioma: Evolutionary Mechanisms and Therapeutic Opportunities

Daniel, Paul; Sabri, Siham; Chaddad, Ahmad; Meehan, Brian; Jean‐Claude, Bertrand J.; Rak, Janusz; Abdulkarim, Bassam

doi:10.3389/fonc.2019.00041

Cited by 124 publications

(97 citation statements)

References 49 publications

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“…When gliomas are challenged with TMZ, recurrent subclones often emerge with inactivating mutations in genes encoding DNA mismatch repair (MMR) enzymes, most commonly MSH2, MSH6, MLH1, and PMS2. Loss of function in these genes leads to failure of MMR mechanisms, which is essential for inducing programmed cell death in tumor cells damage by temozolomide, thus contributing to temozolomide resistance in recurrent tumors [6,12,30]. Tumor mutation burden (TMB) is normally~1 mutation per megabase (Mb) of DNA [1], but MMR defects can lead to a high mutation burden, which has previously been defined as TMB > 20 mutations/Mb DNA [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

The efficacy of DNA mismatch repair enzyme immunohistochemistry as a screening test for hypermutated gliomas

McCord

Steffens

Javier

et al. 2020

acta neuropathol commun

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A subset of gliomas has DNA repair defects that lead to hypermutated genomes. While such tumors are resistant to alkylating chemotherapies, they may also express more mutant neoantigens on their cell surfaces, and thus be more responsive to immunotherapies. A fast, inexpensive method of screening for hypermutated gliomas would therefore be of great clinical value. Since immunohistochemistry (IHC) for the DNA mismatch repair (MMR) proteins Msh2, Msh6, Mlh1, and Pms2 is already used to screen for hypermutated colorectal cancers, we sought to determine whether that panel might have similar utility in gliomas. MMR IHC was scored in 100 WHO grade I-IV gliomas (from 96 patients) with known tumor mutation burden (TMB), while blinded to TMB data. Cases included 70 grade IV GBMs, 13 grade III astrocytomas, 4 grade II astrocytomas (3 diffuse astrocytomas and 1 pleomorphic xanthoastrocytoma), 1 grade I pilocytic astrocytoma, 2 grade III oligodendrogliomas, 7 grade II oligodendrogliomas, and 3 grade I glioneuronal tumors. Eight of 100 tumors showed loss of one or more MMR proteins by IHC, and all 8 were hypermutated. Among the remaining 92 gliomas with intact MMR IHC, only one was hypermutated; that tumor had an inactivating mutation in another DNA repair gene, ATM. Overall accuracy, sensitivity, and specificity for DNA MMR IHC compared to the gold standard of TMB were 99, 89, and 100%, respectively. The strongest correlates with hypermutation were prior TMZ treatment, MGMT promoter methylation, and IDH1 mutation. Among the 8 MMR-deficient hypermutated gliomas, 4 (50%) contained both MMR-lost and MMR-retained tumor cells. Together, these data suggest that MMR IHC could be a viable front-line screening test for gliomas in which immunotherapy is being considered. They also suggest that not all cells in a hypermutated glioma may actually be MMR-deficient, a finding that might need to be considered when treating such tumors with immunotherapies.

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Section: Introductionmentioning

confidence: 99%

The efficacy of DNA mismatch repair enzyme immunohistochemistry as a screening test for hypermutated gliomas

McCord

Steffens

Javier

et al. 2020

acta neuropathol commun

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“…The accumulation of DNA nicks inhibits proliferation by blocking the G2/M cell cycle boundary [75,76]. Our data reaches a contradiction in this experiment, as TMZ needs cells in a high-proliferation state to induce DNA damage, and resting cells, such as GPC1-silenced clones, are seen as a protective mechanism to the genomic alterations caused by the alkylating agent [77]. Nonetheless, GBM cells may present varying degrees of resistance to alkylating agents through the expression of O 6 -methylguanine-DNA-methyltransferase (MGMT) or demethylation of this enzyme's promoter [78,79].…”

Section: Discussionmentioning

confidence: 65%

Glypican-1 in human glioblastoma: implications in tumorigenesis and chemotherapy

Listik

Toma

2020

Oncotarget

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Glioblastoma is one of the most common malignant brain tumors, with which patients have a mean survival of 24 months. Glypican-1 has been previously shown to be overexpressed in human glioblastoma and to be negatively correlated with patient's survival. This study aimed to investigate how glypican-1 influences the tumoral profile of human glioblastoma using in vitro cell line models. By downregulating the expression of glypican-1 in U-251 MG cells, we observed that the cellular growth and proliferation were highly reduced, in which cells were significantly shifted towards G0 as opposed to G1 phases. Cellular migration was severely affected, and glypican-1 majorly impacted the affinity towards laminin-binding of glioblastoma U-251 MG cells. This proteoglycan was highly prevalent in glioblastoma cells, being primarily localized in the cellular membrane and extracellular vesicles, occasionally with glypican-3. Glypican-1 could also be found in cell-cell junctions with syndecan-4 but was not identified in lipid rafts in this study. Glypican-1-silenced cells were much more susceptible to temozolomide than in U-251 MG itself. Therefore, we present evidence not only to support facts that glypican-1 is an elementary macromolecule in glioblastoma tumoral microenvironment but also to introduce this proteoglycan as a promising therapeutic target for this lethal tumor.

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“…Gliomas are primary malignant brain tumors due to carcinogenesis of brain and spinal glial cells (Daniel et al 2019). Pathologically, gliomas are classified as grade I-IV according to World Health Organization (WHO) criteria, with grades I-II considered to be low-grade gliomas (LGG) and grades III-IV high-grade glioma (HGG).…”

Section: Introductionmentioning

confidence: 99%

circKIF4A promotes tumorogenesis of glioma by targeting miR-139-3p to activate Wnt5a signaling

Huo

Wang

Bai

et al. 2020

Mol Med

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Background: Glioma has the characteristics of high incidence and mortality, and is a common malignant tumor of the central nervous system. Circular RNAs (circRNAs) have been reported to play vital roles in progression of cancer including glioma, and circKIF4A is up-regulated in glioma tissues. However, its role and mechanisms in gliomas are unclear.Methods: circKIF4A and miR-139-3p were determined by qRT-PCR. Transwell assay, wound-healing assay, cell colony formation and flow cytometry were performed to measure cell invasion, migration, proliferation and apoptosis. Western blotting was used to evaluate Wnt/β-catenin pathway-related protein. Luciferase reporter assays confirmed the relationship among circKIF4A, miR-139-3p and Wnt5a. Sphere formation was performed to measure the ability of glioma-initiating cells (GICs) spheroid formation. A nude mouse xenograft model was established and immunohistochemical staining was used to detect Ki-67 and Wnt5a levels.Results: circKIF4A and Wnt5a were up-regulated and miR-139-3p was down-regulated in both glioma cells and tissues. circKIF4A promoted Wnt5a expression by sponging miR-139-3p. Knockdown of circKIF4A inhibited the colony formation ability, migration and invasion, and promoted the apoptosis of glioma cells by regulating miR-139-3p. Knockdown of circKIF4A inhibited Wnt/β-catenin signaling pathway and proliferation-related signal via miR-139-3p. Furthermore, knockdown of circKIF4A or overexpression of miR-139 suppressed the ability of sphere formation of GICs and inhibitd Wnt/β-catenin signaling pathway and proliferation-related signal in GICs. Additionally, depletion of circKIF4A decreased the expression level of Wnt5a and Ki-67, inhibited tumorigenesis in xenograft modes.Conclusion: circKIF4A was overexpressed in glioma, and knockdown of circKIF4A suppressed glioma progression via miR-139-3p/Wnt5a axis. The results indicated that circKIF4A may be a potential target for clinical treatment of glioma.

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Temozolomide Induced Hypermutation in Glioma: Evolutionary Mechanisms and Therapeutic Opportunities

Cited by 124 publications

References 49 publications

The efficacy of DNA mismatch repair enzyme immunohistochemistry as a screening test for hypermutated gliomas

The efficacy of DNA mismatch repair enzyme immunohistochemistry as a screening test for hypermutated gliomas

Glypican-1 in human glioblastoma: implications in tumorigenesis and chemotherapy

circKIF4A promotes tumorogenesis of glioma by targeting miR-139-3p to activate Wnt5a signaling

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