The expression of mismatch repair proteins MLH1, MSH2 and MSH6 correlates with the Ki67 proliferation index and survival in patients with recurrent glioblastoma

Stark, Andreas M.; Doukas, Alexander; Hugo, Heinz-Hermann; Mehdorn, H. Maximilian

doi:10.1179/016164110x12645013515052

Cited by 42 publications

(32 citation statements)

References 17 publications

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“…In line with our immunohistochemical findings, Stark et al 30 recently reported on reduced immunoreactivity for MLH1 in recurrent compared to primary glioblastomas. Other authors determined the mRNA expression levels of MSH2, MLH1, PMS1, PMS2 and GTBPT in gliomas and found lower expression relative to normal lymphocytes in variable subsets of patients.…”

Section: Clinical Implications For Mgmt Promoter Methylation Testingsupporting

confidence: 93%

Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas

Felsberg

Thon

Eigenbrod

et al. 2011

Intl Journal of Cancer

263

179

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Epigenetic silencing of the O 6 -methylguanine-DNA methyltransferase (MGMT) gene promoter is associated with prolonged survival in glioblastoma patients treated with temozolomide (TMZ). We investigated whether glioblastoma recurrence is associated with changes in the promoter methylation status and the expression of MGMT and the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 in pairs of primary and recurrent glioblastomas of 80 patients, including 64 patients treated with radiotherapy and TMZ after the first operation. Among the primary tumors, the MGMT promoter was methylated in 31 patients and unmethylated in 49 patients. In 71 patients (89%), the MGMT promoter methylation status of the primary tumor was retained at recurrence. MGMT promoter methylation, but not MGMT protein expression, was associated with longer progression-free survival, overall survival and postrecurrence survival (PRS). Moreover, PRS was increased under salvage chemotherapy. Investigation of primary and recurrent glioblastomas of 43 patients did not identify promoter methylation in any of the four MMR genes. However, recurrent glioblastomas demonstrated significantly lower MSH2, MSH6 and PMS2 protein expression as detected by immunohistochemistry. In conclusion, reduced expression of MMR proteins, but not changes in MGMT promoter methylation, is characteristic of glioblastomas recurring after the current standards of care.Glioblastoma, the most common primary brain tumor in adults, is a rapidly progressive and fatal disease as indicated by a median overall survival (OS) of less than 1 year in a population-based study. 1 The current standard of care comprises surgical resection followed by local radiotherapy as well as concomitant and adjuvant chemotherapy with the DNA methylating agent temozolomide (TMZ). 2 Several independent studies have identified methylation of the O 6 -methylguanine-DNA methyltransferase (MGMT) gene promoter as a biomarker that strongly predicts prolonged progressionfree survival (PFS) and OS in glioblastoma patients treated with TMZ. [3][4][5] The MGMT gene encodes a DNA repair protein that removes alkyl groups from the O 6 -position of guanine (for review, see Ref. 6 ). Thereby, MGMT may counteract the therapeutic efficacy of TMZ and promote treatment failure. Aberrant MGMT promoter methylation may lead to transcriptional repression and lower MGMT protein expression in tumor cells, which may explain the clinical association of MGMT promoter methylation with longer survival of

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Section: Clinical Implications For Mgmt Promoter Methylation Testingsupporting

confidence: 93%

Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas

Felsberg

Thon

Eigenbrod

et al. 2011

Intl Journal of Cancer

263

179

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“…Single-locus MSI was observed in only 3% of glioma patient samples with MSH6 loss, while no sample was classified as MSI-high. This result indicated that the expression of MSH6 was not associated with MSI (11), which has been confirmed by other studies (5,7,9). The inactivation of MSH6 is only associated with the MSI-low phenotype, but not with MSI-high (7).…”

Section: Somatic Msh6 Mutations Glioma Recurrence and Drug Resistancesupporting

confidence: 77%

“…Growing evidence indicates that a deficiency of MMR genes is associated with the recurrence and drug resistance of glioma. Candidate genes of interest include mutL homolog (MLH)1, mutS homolog (MSH)2 and MSH6 (4,5). In particular, MSH6 mutations are considered to play an important role in the recurrence of glioma, acquired resistance to alkylating agents and genome instability (3,6,7).…”

Section: Introductionmentioning

confidence: 99%

Association of MSH6 mutation with glioma susceptibility, drug resistance and progression

Xie

Huang

Zhang

et al. 2016

Molecular and Clinical Oncology

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Abstract. MutS homolog 6 (MSH6) is one of the mismatch repair proteins and is encoded by the MSH6 gene, which is located on chromosome 2 and is 23,806 bp in length, including 10 exons and 83 untranslated regions. The MSH6 protein consists of 1,358 amino acid residues and forms a heterodimer with another mismatch repair protein, MSH2. The MSH2-MSH6 heterodimeric complex is able to recognize base-base substitution and single-base insertion/deletion mismatches. Germline mutations of MSH6 lead to high susceptibility to glioma, as well as a number of benign or malignant tumors in other organs. However, somatic MSH6 mutations are not associated with susceptibility to glioma. Somatic MSH6 mutations usually follow temozolomide treatment and result in resistance to temozolomide. Subsequently, MSH6 mutations cause a hypermutation in the glioma cell genome, which may accelerate tumor progression. Contents1. Introduction 2. Genetic location and function of MSH6 3. Germline MSH6 mutations and cancer susceptibility 4. Somatic MSH6 mutations, glioma recurrence and drug resistance 5. MSH6 mutations lead to tumor genome hypermutation IntroductionGlioma is the most frequent malignant brain tumor in adults. This tumor is characterized by diffuse infiltration of the brain and frequent local recurrence. A malignant tumor is considered to be the result of an accumulation of gene mutations, and tumor progression is driven by additional mutations (1). DNA is constantly exposed to biological, physical and chemical damage that may result in gene mutations; the DNA mismatch repair (MMR) system is responsible for repairing DNA damage. As a result, gene mutations are significantly more frequent in MMR-deficient cells (2,3). Theoretically, mutations in the MMR system may cause additional mutations in numerous other genes, initiating a cascade of mutations throughout the cancer genome. Some of these mutations may confer selective advantages, which enable the mutated cells to proliferate and achieve clonal dominance (4). Growing evidence indicates that a deficiency of MMR genes is associated with the recurrence and drug resistance of glioma. Candidate genes of interest include mutL homolog (MLH)1, mutS homolog (MSH)2 and MSH6 (4,5). In particular, MSH6 mutations are considered to play an important role in the recurrence of glioma, acquired resistance to alkylating agents and genome instability (3,6,7). The aim of the present study was to review the association between MSH6 mutations and glioma. Genetic location and function of MSH6Mismatches inevitably occur during DNA replication. Prokaryotic as well as eukaryotic organisms are equipped with enzymatic systems to repair these mismatches. The bacterial MutHLS system repairs single-base mismatches and small insertion/deletions. Eukaryotic cells possess respective counterpart enzymes to repair mismatches. In yeast, mammalian cells and other organisms, the MMR systems are similar to the prokaryotic MutHLS system, and are therefore named MSHs and MLHs (8). Certain MMR proteins have unique functions...

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“…Second, two studies have shown by immunohistochemistry that small subpopulations of MLH1-negative cells commonly arise in primary GBM. One study showed that MLH1-negative cells were enriched after TMZ treatment in recurrent tumors (Stark et al 2010). The second study showed that cells lacking PMS2 were enriched in recurrent tumors (Felsberg et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Multiplex mapping of chromatin accessibility and DNA methylation within targeted single molecules identifies epigenetic heterogeneity in neural stem cells and glioblastoma

et al. 2013

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Human tumors are comprised of heterogeneous cell populations that display diverse molecular and phenotypic features. To examine the extent to which epigenetic differences contribute to intratumoral cellular heterogeneity, we have developed a high-throughput method, termed MAPit-patch. The method uses multiplexed amplification of targeted sequences from submicrogram quantities of genomic DNA followed by next generation bisulfite sequencing. This provides highly scalable and simultaneous mapping of chromatin accessibility and DNA methylation on single molecules at high resolution. Long sequencing reads from targeted regions maintain the structural integrity of epigenetic information and provide substantial depth of coverage, detecting for the first time minority subpopulations of epigenetic configurations formerly obscured by existing genome-wide and population-ensemble methodologies. Analyzing a cohort of 71 promoters of genes with exons commonly mutated in cancer, MAPit-patch uncovered several differentially accessible and methylated promoters that are associated with altered gene expression between neural stem cell (NSC) and glioblastoma (GBM) cell populations. In addition, considering each promoter individually, substantial epigenetic heterogeneity was observed across the sequenced molecules, indicating the presence of epigenetically distinct cellular subpopulations. At the divergent MLH1/EPM2AIP1 promoter, a locus with three well-defined, nucleosome-depleted regions (NDRs), a fraction of promoter copies with inaccessible chromatin was detected and enriched upon selection of temozolomide-tolerant GBM cells. These results illustrate the biological relevance of epigenetically distinct subpopulations that in part underlie the phenotypic heterogeneity of tumor cell populations. Furthermore, these findings show that alterations in chromatin accessibility without accompanying changes in DNA methylation may constitute a novel class of epigenetic biomarker.

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The expression of mismatch repair proteins MLH1, MSH2 and MSH6 correlates with the Ki67 proliferation index and survival in patients with recurrent glioblastoma

Abstract: Our results indicate a potential important role of MLH1 and MSH6 in glioblastoma progression. Specific attention should be given on the role of MLH1 and MSH6 in patients with glioblastoma recurrence during temozolomide treatment.

Cited by 42 publications

References 17 publications

Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas

Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas

Association of MSH6 mutation with glioma susceptibility, drug resistance and progression

Multiplex mapping of chromatin accessibility and DNA methylation within targeted single molecules identifies epigenetic heterogeneity in neural stem cells and glioblastoma

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