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  Table of Contents  
REVIEW ARTICLE
Year : 2015  |  Volume : 52  |  Issue : 4  |  Page : 568-573
 

Therapy and progression – induced O6-methylguanine-DNA methyltransferase and mismatch repair alterations in recurrent glioblastoma multiforme


Department of Pathology, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication10-Mar-2016

Correspondence Address:
C Sarkar
Department of Pathology, All India Institute of Medical Sciences, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.178403

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 » Abstract 

Despite multimodality treatment protocol including surgical resection, radiotherapy, and chemotherapy in patients with glioblastoma multiforme (GBM), most suffer from treatment failure and tumor recurrence within a few months of initial surgery. The effectiveness of temozolomide (TMZ), the most commonly used chemotherapeutic agent, is largely dependent on the methylation status of the promoter of the gene O6-methylguanine-DNA methyltransferase (MGMT) and the integrity of the mismatch repair (MMR) system. Changes in these regulatory mechanisms at the time of recurrence may influence response to therapy. Deciphering the molecular mechanisms of resistance to these drugs may in future lead to improvised patient management. In this article, we provide an update of the spectrum of molecular changes that occur in recurrent GBMs, and thus may have an impact on patient survival and treatment response. For review, electronic search for the keywords “Recurrent GBM”, “Recurrent GBM AND MGMT” “Recurrent glioma AND MGMT”, “Recurrent GBM AND MMR” and “Recurrent glioma AND MMR”, “Recurrent GBM AND MMR” and “Recurrent glioma AND MMR” was done on PubMed and relevant citations were screened including cross-references.


Keywords: Glioblastoma, mismatch repair, molecular, recurrent gliomas, O6- Methylguanine-DNA methyltransferase


How to cite this article:
Agarwal S, Suri V, Sharma M C, Sarkar C. Therapy and progression – induced O6-methylguanine-DNA methyltransferase and mismatch repair alterations in recurrent glioblastoma multiforme. Indian J Cancer 2015;52:568-73

How to cite this URL:
Agarwal S, Suri V, Sharma M C, Sarkar C. Therapy and progression – induced O6-methylguanine-DNA methyltransferase and mismatch repair alterations in recurrent glioblastoma multiforme. Indian J Cancer [serial online] 2015 [cited 2019 Dec 13];52:568-73. Available from: http://www.indianjcancer.com/text.asp?2015/52/4/568/178403





 » Introduction Top


Glioblastoma multiforme (GBM) is the most common and lethal cancer involving the central nervous system. Substantial research efforts have highlighted the existence of distinct molecular subclasses, thus setting off the need to explore new avenues of therapeutic intervention.[1] Nonetheless, the prognosis of patients with GBM remains poor with nearly all patients developing a recurrence within few months of initial therapy with the median survival time being less than 16 months.[2] Many researchers have investigated the possible mechanisms of resistance that contribute to tumor progression and recurrence. Although a plethora of molecular alterations have been elucidated in GBMs, in view of the dismal prognosis there is a pressing need to understand the molecular changes that occur during treatment and determine therapeutically resistant recurrences.[3] O6-methylguanine-DNA methyltransferase (MGMT) methylation and DNA mismatch repair (MMR) system are some of the key mechanisms that have generated interest among researchers to evaluate their role in recurrent GBMs for prognostication and therapeutic monitoring.

MGMT is a DNA-repair enzyme that acts by removing the alkyl groups at the O6 position of guanine introduced by alkylating drugs such as temozolomide (TMZ).[4] Epigenetic silencing of MGMT by promoter methylation has been associated with increased chemoresposiveness and longer survival in newly diagnosed GBM patients treated with these drugs.[5] Despite these novel developments, median overall survival (OS) has improved only marginally to about 21 months in patients with GBM having a methylated MGMT promoter.[5] Resistance to alkylating drugs seems to be more complex than a mere dependence on MGMT status. Thus, recent studies have tried to analyze the impact of MGMT profile in patients with recurrent GBM and its possible impact on survival and also to assess its alterations between the first and second surgeries.[6],[7],[8],[9],[10],[11]

Besides MGMT, the MMR system is another major biomarker of response to alkylating therapy. MMR deficiency results in tolerance to these drugs irrespective of the MGMT status; thus, determining the tumor DNA MMR activity may help identify resistant cases.[12],[13],[14] Additionally, TMZ therapy has been reported to induce mutations in MMR genes in GBM at recurrence, in turn leading to tumor progression.[15],[16],[17],[18],[19]

This review provides an insight into the alterations in MGMT and MMR status in GBMs with therapy and with disease progression, knowledge of which might be useful in predicting resistance to therapy. Pubmed was searched for articles using the keywords “Recurrent GBM”, “Recurrent GBM AND MGMT”, “Recurrent glioma AND MGMT”, “Recurrent GBM AND MMR” and “Recurrent glioma AND MMR”. No limits were activated before the search and the date of the queries was set at “any date”. Of the nearly 500 citations thus enlisted, articles relevant to the topic were screened.

O6-methylguanine-DNA methyltransferase promoter methylation in recurrent glio MGMT promoter methylation blastoma multiforme

Esteller et al.[20] provided, for the first time, evidence supporting a role of MGMT promoter methylation in predicting response to alkylating drugs. They could demonstrate increased sensitivity to carmustine along with an improved OS and time to progression.[20] Subsequently, Hegi et al.,[5] in their study on 206 patients enrolled in the study conducted by European Organisation for the Research and Treatment of Cancer and the National Cancer Institute of Canada (EORTC trial 26981/22981 NCIC trial CE.3) demonstrated that epigenetic silencing of the MGMT gene by promoter methylation in GBM patients treated with the combined regime including TMZ and radiotherapy (RT) had a median survival of 21.7 months in comparison to 12.7 months in those with unmethylated MGMT.[5] The five-year survival analysis of the data of EORTC/NICC trial also showed that methylation of the MGMT promoter was the strongest predictor for outcome and benefit from TMZ.[21] However, eventually nearly all GBMs relapse irrespective of the MGMT methylation profile.[22] Various authors have assessed changes in MGMT promoter methylation status in paired initial and recurrent GBM samples [Table 1]. Results, however, have been highly variable. On a critical analysis of the available data, MGMT methylation status at first recurrence appears to remain identical to that in the initial tumor in most patients [Table 1].[6],[8],[9],[10],[11] Although Metellus et al.,[8] in their study on 22 recurrent GBMs, did not find any change in the promoter methylation status, 14% (3/22) of their cases showed an increase MGMT protein expression by immunohistochemistry (IHC).[8]
Table 1: Change in O6--methylguanine--DNA methyltransferase promoter methylation status at recurrence in glioblastoma multiforme

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Brandes et al.[9] interestingly found MGMT shifts from methylated to unmethylated to be more frequent in patients treated with a combination of TMZ and RT, in contrast to those given only RT (P = 0.03).[9]

Christmann et al.,[10] in 2010, determined MGMT activity, promoter methylation, and immunoreactivity in pretreatment and recurrent GBMs and in anaplastic astrocytomas. Of these, there were only nine cases from paired GBM tumor samples. MGMT promoter methylation was assessed by methylation-specific polymerase chain reaction (MSP) and MGMT activity by a radioactive assay. Alteration in MGMT activity was observed in 78% (7/9) (six showing an enhancement and one diminution). This change, however, was unrelated to MGMT promoter methylation.[10] On comparing data from patients treated with RT alone (65.4 fmol/mg) with those in whom TMZ was included in the treatment regimen (135.4 fmol/mg), increase in the MGMT activity was noted to be more in the latter group.[10]

Felsberg et al.[11] looked for MGMT protein immunoexpression in 40 patients, and demonstrated increased immunoreactivity scores in 32.5%, (13/40) decreased scores in 27.5%, (11/40) and no change in 40% (16/40). A significant change in immunoreactivity was observed in patients treated with TMZ versus the one treated only with RT (P = 0.035).[11]

Wiewrodt et al.,[7] in 2008, measured MGMT activity using a radioactive assay in 40 cases of primary GBM. Paired tumors resected at first (n = 18), second (n = 7), and third recurrence (n = 4) were also analyzed. Interestingly, an increase in the MGMT activity was detected at each subsequent recurrence. Similar to some of the previous studies, increase in activity was significantly higher (P < 0.05) in the RT + chemotherapy (CT) group than in the only RT patients.[7]

The main drawback of most of these papers is their small sample size, from which definitive conclusions are difficult to be drawn. The two major studies in the field are those of Brandes et al.[9] and Felsberg et al.,[11] results of which are apparently contradictory.

As discussed already, MGMT expression at the protein level has also been analyzed by various authors.[7],[8],[10],[11] However, the differences in the results may be attributed again to the small sample size [8],[10] and also to the method used.[7],[8],[10],[11] The alteration in MGMT promoter methylation and protein expression at recurrence may also be explained by well-known issues such as intra-tumoral variability, contamination of the tumor tissue with normal tissue and/or inflammatory cells and/or necrosis, and selective therapy-induced tumor cell death.[8],[9] However, in two recent studies, no significant difference was found in MGMT promoter methylation assessed in tissue taken from different regions of the same tumor using MSP and sequencing, thus ruling out intra-tumor heterogeneity as a plausible cause of change at recurrence.[23] Interestingly, recent studies have shown that there are distinct stem cell populations that, despite the similar MGMT promoter methylation status, differ in MGMT protein expression and thus also in their susceptibility to CT[24],[25] Selective survival of tumor cells with high MGMT expression during alkylating agent therapy may, hence, lead to a change in MGMT status at recurrence.[7],[8],[9],[10] Gene modifications induced due to therapy and/or due to disease progression are other plausible mechanisms of a shift in MGMT profile at second surgery. MGMT gene in rodents and MGMT promoter in humans have been shown to be induced by alkylating agents as well as by RT in various experimental studies.[26],[27],[28],[29],[30],[31] The existence of this phenomenon in vivo in human normal and tumor tissue is unknown, but if present may explain the increase in MGMT protein immunoexpression and activity at recurrence demonstrated in some studies. Moreover, a greater upregulation of MGMT activity observed in patients treated with alkylating agents in addition to RT than in those with RT alone may be explained by a possible synergistic action of these DNA-damaging agents, when used in conjunction.[7],[8],[10] The role of other methylating sites or gene-regulating mechanisms besides CpG methylation has also been suggested.[10]

The use of MGMT profile in predicting chemoresponsiveness and survival in patients with recurrent GBM has also been evaluated. Brandes et al.[9] have documented that MGMT methylation status in the second tumor specimen may not have any prognostic relevance in contrast to that in the initial tumor.[8] Similar results were obtained by Sadones et al.[32] in their study on 22 cases of recurrent GBM.[32] In contrast, Felsberg et al.[11] reported MGMT promoter methylation at both initial and second surgeries to be prognostically relevant, however, due to the absence of any shift in methylation status at recurrence, the authors argued against the necessity of a repeat MGMT testing.[11] However, Wiewrodt et al.[7] found an increased MGMT activity at second and third recurrences, which correlated with enhanced chemoresistance.[7] Metellus et al.[8] also found MGMT methylation at recurrence to be an important determinant of improved survival in GBMs.[8] Nagane et al.,[33] in 2007, evaluated the prognostic significance of MGMT protein expression by western blotting in 30 patients with recurrent GBM. Improved progression-free survival (PFS) (P = 0.016) and OS (P = 0.019) were observed in patients with low MGMT protein score than in those with high expression. However, MGMT protein expression in the initial tumor was not analyzed.[33]

Thus, again the differences in the results on prognostic impact of MGMT profile at the time of recurrence may be due to the method used as well as the variable number of patients included.

DNA mismatch repair genes alterations in recurrent glioblastoma multiformes

Eukaryotic MMR system includes the MutS-homolog (MSH) and the MutL-homolog (MLH) proteins, which recognize base: base mismatches and nucleotide loops. MutSα, formed by MSH2 and MSH6, is the major heterodimeric complex of the MMR system. MutSβ comprises MSH2 and MSH3 and MutLα of MLH1 and PMS2 (Post Meiotic Segregation increased 2) proteins.[34] O6 alkyl adducts introduced by alkylating agents have a tendency to cross-link with thymine during DNA replication, generating GC > AT transitions. These G/T mismatches are recognized by the DNA MMR protein complex MutSα, which in turn results in the activation of the Ataxia telengiectasia and Rad3-related protein (ATR)/Checkpoint kinase 1 (Chk 1) S/G2-phase checkpoint pathway, ultimately resulting in the induction of apoptosis.[35] This pathway is thought to mediate the cytotoxic effect of alkylating drugs. Thus, MGMT and MMR have opposite actions on the DNA O6-methylguanine. MGMT repairs the methylated base, whereas MMR induces cell death. Hence, although loss of MGMT increases chemosensitivity to these drugs, a deficient MMR system protects the cells from their cytotoxic action. Failure to repair mismatches in the latter situation leads to increased resistance of cells to the killing effects of alkylating agents, thereby contributing to tumor recurrence.[36] In addition, loss of MMR function leads to increased mutagenesis,[36] with the subsequent development of a “hypermutation” phenotype in recurrent malignant gliomas.[15],[17]

In 2006, Hunter et al.[15] sequenced genomic DNA from nine high-grade gliomas comprising six primary cases [4 primary GBMs, 1 Anaplastic Oligodendroglioma grade III (AO), and 1 Anaplastic Oligoastrocytoma grade III (AOA)] and three recurrent GBMs. None of the primary GBMs showed MSH6 mutation. However, large numbers of somatic mutations, including MSH6 mutation, were observed in two recurrent GBMs, who had received alkylating agent treatment [Table 2]. The pattern of these mutations was also similar to that induced by alkylating agents in experimental systems. Primary tumor tissue available in one of these two cases also lacked MSH6 gene mutation. The authors suggested that once MSH6 is inactivated, it confers resistance to alkylating drugs. In the wake of continued exposure to alkylator CT, there is a selection of clone of resistant tumor cells, which then expand and lead to recurrence.[15] Thus, Hunter et al.[15] concluded that in the presence of MSH6 inactivation, alkylating agents, instead of behaving tumoricidal, induce neoplastic progression.[15]
Table 2: Change in mismatch repair mutation status at recurrence in glioblastoma multiforme

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In 2008, the cancer genome  Atlas More Details (TCGA) research network study [17] analyzed DNA copy number, gene expression, and DNA methylation aberrations in 206 GBMs. A significant proportion (37%, 7/19) of their recurrent GBMs, which had been pretreated with alkylating agents, had a hypermutator phenotype [Table 2]. Of these, 97% (6/7) tumors harbored mutations in a minimum of one of the four MMR genes, MSH2, MSH6, MLH1, or PMS2. Specifically, MSH6 gene mutation was found in five of these cases. Interestingly, none of the 72 newly diagnosed GBM cases were hypermutated [Table 2]. Another interesting finding was the positive correlation between MGMT silencing and the hypermutator phenotype. Tumor samples treated with alkylating agents displayed MGMT promoter methylation and also showed most (81%) of the somatic mutations of G: C to A: T transition type in non-CpG dinucleotides. In contrast, tumors having an unmethylated MGMT showed almost an even distribution of mutations in CpG and non-CpG islands. Thus, MGMT methylation shifted the mutation spectrum of treated samples to a preponderance of G: C to A:T transition type at non-CpG dinucleotide sites. The authors, hence, concluded that both MMR loss and MGMT silencing influence the frequency as well as pattern of somatic mutations in treated GBMs.[17]

Later, in 2009, Yip et al.[19] performed MSH6 sequence analysis in four matched pre- and post-CT GBMs identified by TCGA as having post-treatment MSH6 mutations. The authors confirmed the presence of MSH6 mutations in the post-CT specimens; however, all the pretreatment samples lacked the genetic alteration. These authors also exposed the MSH6-wildtype GBM line to TMZ, resulting in the development of TMZ-resistant clones, which when assessed by Western Blot displayed decreased MSH6 protein expression resulting from a c. 3656C > T MSH6 somatic mutation. TCGA had also documented presence of the same mutation in two of their seven recurrent GBM hypermutated samples.[19] Yip et al.[19] also used the lentiviral shRNA approach to knock down MSH6 protein in the GBM line, which lead to increased refractoriness to TMZ cytotoxicity. Furthermore, reconstitution of MSH6 protein restored the susceptibility of the cells to TMZ. The authors also observed that all the cases and cell lines included in the study had an inactivated MGMT. Thus, once MGMT activity is down regulated, susceptibility to TMZ was mainly due to MSH6.[19]

Similar results had been obtained by Cahill et al.[16] in 2007 [Table 2]. They also assessed MSH6 protein expression immunohistochemically in matched pre- and post-CT samples and showed loss of expression in 41% (7/17) of the recurrent samples in contrast to none of the primary resections. Similar results were obtained with immunohistochemical analysis. All the eight post-RT cases showed MSH6 immunoexpression. However, 75% (3/4) post-RT+TMZ patients lacked MSH6 immunoexpression. During the course of TMZ treatment, using 3-D MRI the authors demonstrated that MSH6-negative GBMs progressed more rapidly than the MSH6-positive tumors (P = 0.020).[16]

Thus, the studies conducted so far have emphasized that MSH6 gene mutations seen at recurrence may be the result of alkylating agents used, mediating unresponsiveness of a selected clone of tumor cells toCT, and hence resulting in a survival advantage in the wake of continued alkylatingCT.

Despite these results, there are a few publications that do not support the role of MSH6 deficiency in TMZ resistance. In 2008, Maxwell et al.[18] sequenced MSH6 gene in 27 TMZ + RT failure cases, including 21 GBMs. One or more variations from the canonical DNA sequence resulting in amino acid change were found in 52% (14/27) cases, most of which were heterozygous and did not result in MSI. The authors suggested that many of these mutations could be undocumented population variances. They also demonstrated detectable MSH6 mutations in both pre- and post-treatment tumor specimens in two GBM cases with available paired samples [Table 2]. The authors thus postulated that mechanisms other than the MMR system might be involved in mediating alkylating drug resistance.[18]

Conversely, Stark et al.,[37] in 2010, demonstrated MSH6 positivity in the initial GBM specimen as detected by IHC to be a poor prognostic indicator.[37] The authors also evaluated the role of MMR proteins other than MSH6 in GBM progression, and found a decreased MLH1 immunoexpression at recurrence in the 42 paired GBM samples included in their study. They also documented a significant association of the ki67 labeling index with the expression of MLH1, MSH2, and MSH6 proteins in the initial tumors as well as with MLH1 and MSH2 proteins in the recurrent specimens. Significantly, besides MSH6, MLH1 immunopositivity in the primary specimens also correlated with a poorer survival.[37]

In 2011, Felsberg et al.[11] reported recurrent GBMs to have significantly decreased immunoexpression of MSH2, MSH6, and PMS2 proteins, in the absence of a methylated promoter in any of the four MMR genes. They suggested that a reduced MMR expression is frequent in GBMs and may contribute to decreased susceptibility to treatment and eventually to recurrence.[11]

However, in 2009, Metellus et al.[8] did not find any correlation of MLH1 and MSH2 protein immunoexpression with PFS or OS in GBM patients both at first surgery and after recurrence. Additionally, most of the primary tumors (95%; 100%) as well as recurrent specimens (100%; 100%) were immunopositive for both MLH1 and MSH2.[8]

In 2007, Gömöri et al.[38] evaluated 11 paired GBM samples and did not find MLH1 gene mutation or promoter methylation in any [Table 2]. They, instead, documented promoter methylation in a subset of their low-grade gliomas, suggesting MLH1 gene inactivation by promoter methylation to be an early event in a proportion of glial tumors.[38]

Defects in the MMR system result in errors, which accumulate during replication resulting in microsatellite instability (MSI). It may be classified as high (MSI-H) when more than two of the five loci used in Polymerase chain reaction (PCR) to assess MSI show instability or as low (MSI-L) when none to two loci are unstable.[15] Interestingly, none of the cases of recurrent GBM with MSH6 mutation in the series by both Hunter et al.[15] and Yip et al.[19] showed MSI-H.[15],[19] In hereditary non-polyposis colorectal cancer, MSH6 mutation has been found to be linked with MSI-L.[39],[40] The absence of MSI-H in cases with MSH6 mutation has been explained by the presence of a functional dichotomy between DNA repair function and induction of cancer cell death via apoptosis following CT.[41] MSH6 also functions exclusively in the recognition of single-base-pair mismatches and does not play any role in their subsequent repair.[42] Another suggested cause of MSI-L is the compensation of the loss of MutSα activity due to destabilizing MSH6 mutations by an increased MutSβ (MSH2/MSH3) heterodimer, which may perform MMR, and thus maintain a functional MMR.[18],[43] Yip et al.[19] have thus indicated that the role of MSH6 in TMZ response is independent of MSI.[19] However, importantly, most of the studies on recurrent GBMs have a small sample size, especially those based on molecular genetics, and thus, difficult to derive a conclusion from. In addition, as post-surgery radioCT acts on the peritumoral theoretically “normal tissue”, there are reports indicating that the peritumor tissue, independently of the presence of neoplastic cells, may present signs of transformation. The results from these studies also highlight the fact that the biologic commitment of 'penumbra' cells appear to be the most relevant factor for tumor recurrence.[44],[45],[46],[47]


 » Conclusions Top


Since all GBMs recur leading to patient death, knowledge of the molecular changes occurring during disease progression is mandatory for optimizing therapeutics. Understanding the roles of MGMT methylation and DNA MMR system in determining tumor response to treatment may help in developing targeted therapy having increased treatment response combined with less toxicity. However, as our knowledge on GBM is still too limited, multi-institutional studies on paired tumor samples may be required to further elucidate the mechanistics of recurrence.

 
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    Tables

  [Table 1], [Table 2]

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