Research ArticleClinical Studies

Association of MGMT Gene Promoter Methylation With Clinicopathological Parameters in Patients With Wild-type IDH Glioblastoma

MOONSIK KIM, JIHWAN YOO, JONG HEE CHANG and SE HOON KIM
Anticancer Research January 2022, 42 (1) 335-341; DOI: https://doi.org/10.21873/anticanres.15490

Abstract

Background: The methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter plays a key role in response to temozolomide chemotherapy and disease prognosis in patients with wild-type isocitrate dehydrogenase (IDH) glioblastoma (GBM). Patients and Methods: The MGMT promoter methylation status and its association with clinicopathological parameters were retrospectively analysed in a cohort of 316 patients with GBM with wild-type IDH. Results: MGMT methylation was significantly associated with ATRX chromatin remodeler (ATRX) loss and completion of the standard Stupp protocol. The median durations of overall and progression-free survival for the unmethylated, low-methylated (10-39%), and hypermethylated (≥40%) groups were 15, 23, and 30 months and 11, 18, and 21 months, respectively. However, the improvement in the survival of the hypermethylated group was not statistically significant. Conclusion: We suggest a possible association between MGMT methylation status and ATRX mutations in GBM with wild-type IDH.

Key Words

Glioblastoma (GBM) is the most common malignant brain tumour in adults and manifests with a hostile clinical behaviour (1). Despite aggressive therapy, its prognosis continues to be dismal, with an overall survival (OS) of 15-17 months (2). The Stupp protocol is the standard of care for GBM treatment and comprises neurosurgical resection followed by concomitant chemoradiation and adjuvant chemotherapy with temozolomide (3, 4), a cytotoxic alkylating agent that causes double-stranded DNA breaks in cells. Previous randomized trials have shown that methylation of the O6-methylguanine-DNA methyl-transferase (MGMT) promoter is significantly associated with higher survival rates in temozolomide-treated patients with GBM (3-6). The DIRECTOR trial indicated temozolomide rechallenge as a possible treatment for recurrent GBM with a methylated MGMT promoter (7). Additionally, the NOA-09 trial suggested that a combined lomustine/temozolomide treatment can improve prognosis compared to conventional temozolomide therapy (5).

However, while the importance of MGMT promoter methylation for determining the prognosis of GBM is clear, its association with clinicopathological parameters has not been fully elucidated. In addition, previous studies have been hampered by the fact that GBM can be divided into subgroups with mutant and wild-type isocitrate dehydrogenase (IDH), which have significantly different biological behaviours and clinical courses (8, 9). Currently, only a few studies have focused particularly on MGMT methylation in GBM with wild-type IDH (10).

The MGMT methylation cut-off value of ≥10% based on pyrosequencing is widely used to dichotomize the MGMT promoter methylation status as ‘methylated’ or ‘unmethylated’ (10-12); however, it is still unclear if further subclassification of the MGMT methylation status might confer additional survival benefits in patients.

In this retrospective study, we investigated the association between MGMT methylation status and clinicopathological characteristics in patients with wild-type IDH GBM. Additional cut-off values that might have prognostic implications for patients were also analysed.

Patients and Methods

Patient selection. We retrieved information on 316 patients with GBM who underwent surgical resection between May 2016 and December 2019 from the computerized files generated during the surgical pathology diagnosis. GBM diagnosis was determined according to the 2016 World Health Organization classification of central nervous system tumours (1). All cases were reviewed and confirmed by two specialized neuro-oncopathologists (authors, MK, and SHK). The 1p/19q status was evaluated using fluorescence in situ hybridization (FISH). IDH mutational status was assessed by immunohistochemical analysis of IDH1 R132H and Sanger sequencing of IDH1 and IDH2. Clinicopathological data including age at diagnosis, sex, Karnofsky performance status, extent of tumour resection and residual tumour volume, types and duration of adjuvant therapy, follow-up time, overall survival (OS), and progression-free survival (PFS) were obtained from the electronic medical records of the hospital. The study plan was reviewed and approved by the Institutional Review Board of Severance Hospital (4-2020-0547).

Immunohistochemistry. Formalin-fixed, paraffin-embedded (FFPE) slices of tumours from study patients were deparaffinized and rehydrated with xylene and alcohol solution. The slices were stained with antibodies against ATRX (1:150, polyclonal; Atlas Antibodies, Bromma, Sweden), IDH1 R132H (1:80, H09; Hamburg, Germany), Ki-67 (1:150, clone MB-1; Dako, Glostrup, Denmark), and p53 (1:300, clone DO7; Novocastra, Leica Biosystems, Newcastle Ltd., Newcastle Upon Tyne, UK). After chromogenic visualization using an ultraView Universal DAB Detection Kit (Ventana Medical Systems, Oro Valley, AZ, USA) or EnVision FLEX/HRP (Dako), slices were counterstained with hematoxylin. The stained slides were reviewed by MK and SHK. Samples were considered positive for p53 when >10% of tumour cells showed nuclear expression. ATRX loss was defined as >90% of tumour cells showing negative nuclear staining. IDH1 R132H immunostaining was considered positive when tumour cells showed diffuse and strong staining in the cell membrane.

Determination of epidermal growth factor receptor (EGFR) amplification with FISH. To determine EGFR amplification, FISH assays were performed on FFPE tumour samples. FISH studies were performed using the EGFR/CEP7 FISH Probe Kit (Abbott Molecular, Des Plaines, IL, USA), according to the manufacturer’s instructions. EGFR amplification was defined as an EGFR:CEP7 ratio of ≥2.0. At least 60 tumour cells were counted in each case.

Tumour DNA extraction and bisulphite modification. Areas with >80% tumour cells were chosen for MGMT promoter methylation analysis. Genomic DNA was extracted from cryopreserved tumour tissues and FFPE samples using QIAamp DNA Mini and QIAamp DNA FFPE Tissue Kits (Qiagen, Hilden, Germany), respectively. DNA concentration was quantified using a NanoDrop ND-1000 spectrophotometer (NanoDrop Technologies, Houston, TX, USA). Furthermore, 100 ng of DNA was subjected to bisulphite conversion using an Epitect Bisulphite kit (Qiagen) according to the manufacturer’s protocol.

MGMT promoter pyrosequencing. Pyrosequencing was performed using a Therascreen MGMT Pyro Kit (Qiagen) according to the manufacturer’s instructions. The average percentage of methylated alleles was determined using the mean value of the individual methylation percentage. For every pyrosequencing run, standardized positive and negative controls were also included. An MGMT methylation cut-off value of ≥10% was used to dichotomize the MGMT promoter methylation status into two as ‘methylated’ or ‘unmethylated’.

Statistical analysis. Relationships between clinicopathologic parameters were evaluated using the chi-square test for categorical parameters and Fisher’s exact test for parameters with an expected frequency <5. OS and PFS were evaluated using the Kaplan–Meier method. Statistical differences in survival times were determined using log-rank tests. Statistical significance was set at p<0.05. All statistical analyses were conducted using R package (version 3.4.3, http://www.R-project.org).

Results

Patient cohort. A total of 316 cases were selected. The median age was 61 years, with 190 men (60.1%) and 126 women (39.9%) The median Karnofsky performance score was 80 (range=40–100). Among the 316 patients, 25 (7.9%) underwent biopsy, 83 (26.3%) underwent subtotal resection, and 208 (65.8%) underwent gross total resection. Of the 316 patients, 276 (87.3%) completed the standard Stupp protocol. MGMT promoter methylation was found in 35.8% of the patients (113/316).

Association of clinicopathologic characteristics with MGMT methylation status. We then classified the patient cohort according to MGMT methylation status and compared their clinicopathological characteristics (Table I). Among the clinicopathological parameters, ATRX loss was significantly associated with MGMT promoter methylation (p=0.010). Patients who completed the standard Stupp treatment were more frequently found in the group with methylated MGMT (p=0.025). Age, sex, Karnofsky performance score, mode of surgery, p53 mutational status, EGFR amplification, and Ki-67 labelling index were not related to MGMT methylation status.

View this table:
Table I.

Patient cohort characteristics based on O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status.

Survival analysis on the basis of MGMT methylation status. The median OS for groups with methylated and unmethylated MGMT was 24 and 15 months, respectively (p=0.004), and the median PFS was 19 and 11 months, respectively (p<0.001) (Figure 1).

Figure 1.
Figure 1.

Overall (A) and progression-free (B) survival of patients with glioblastoma with wild-type isocitrate dehydrogenase based on the O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status.

We further investigated whether the extent of MGMT promoter methylation might be used for further prognostic stratification, other than by dichotomizing MGMT promoter status as being methylated or unmethylated. Median OS and PFS were evaluated for the following methylation groups: 0-9%, 10-19%, 20-29%, 30-39%, and ≥40%. The median OS and PFS for each group were 15, 22, 20, 24, and 30 months and 11, 18, 15, 20, and 21 months, respectively. For OS, Kaplan–Meier analysis showed the group with 0-9% methylation to fare significantly better than the group with ≥40% methylation (p=0.004). For PFS, significantly better survival was observed for the group with 0-9% methylation compared with 10-19% (p=0.039), 30-39% (p=0.044), and ≥40% (p=0.046) methylation (Figure 2). As both OS and PFS significantly differed between 0-9% and ≥40% mean MGMT methylation, we reclassified patients into unmethylated (0-9%), low-methylated (10-40%), and hypermethylated (≥40%) groups. The median OS and PFS for each group were 15, 23, and 30 and 11, 18, and 21 months, respectively. In Kaplan– Meier analysis, the survival differences were significant for unmethylated compared with the low-methylated group (p=0.028, OS; p=0.006, PFS) and compared with the hypermethylated group (p=0.018, OS; p=0.046, PFS); however, there was no statistically significant difference between low-methylated and hypermethylated (p=0.137, OS; p=0.603, PFS) (Figure 3).

Figure 2.
Figure 2.

Overall (A) and progression-free (B) survival of patients with glioblastoma with wild-type isocitrate dehydrogenase according to O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation group: 0-9%, 10-19%, 20-29%, 30-39%, and ≥40%.

Figure 3.
Figure 3.

Overall (A) and progression-free (B) survival curves for patients with glioblastoma with wild-type isocitrate dehydrogenase based on O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation group: UM: Unmethylated (0-9%); LM: low-methylated (0-39%); HM: hypermethylated (≥40%).

Discussion

In the present cohort with wild-type IDH GBM, we investigated the association between MGMT promoter methylation status and clinicopathological parameters of patients. MGMT is a DNA repair enzyme that can repair alkylating agent (e.g., temozolomide)-induced O6-methylguanine back to guanine (13). MGMT promoter methylation is associated with low protein expression levels, an enhanced response to alkylating agents, and a better prognosis (14-16). Among the reports on MGMT promoter methylation status, only few have strictly focused on patient cohorts limited to IDH-wild-type GBM (10).

We demonstrated that MGMT promoter methylation is frequently associated with ATRX loss. ATRX is a part of the SWI/SNF family of chromatin remodelling proteins (17). In combination with death domain associated protein (DAXX), ATRX maintains genomic stability by depositing H3.3 in pericentromeric and sub-telomeric regions (18). ATRX loss promotes alternative lengthening of telomeres (19) and has been reported in various types of cancer, including gliomas (20-22). Mutations in ATRX rarely occur in wild-type IDH GBM. Brennan et al. reported only three cases (1.0%) of ATRX-mutant IDH-wild-type GBMs in a total of 291 cases (23). In our study, ATRX loss was found in 8.8% (10/113) of those of the methylated group, whereas only 2.5% (5/203) were found in the unmethylated group. Currently, only few studies have reported an association between MGMT promoter methylation and ATRX mutations (24). The possible mechanisms underlying this association must be clarified in future studies.

In addition, we show that MGMT promoter methylation was also more frequently found in patients who completed the standard Stupp protocol (38.4%, 106/276) than in those who discontinued the protocol (17.5%, 7/40). Since MGMT promoter methylation is a powerful predictive biomarker for the response to alkylating agents (16), MGMT methylation status may have affected the completion of the Stupp protocol in patients with GBM.

Currently, a pyrosequencing-based cut-off value of ≥10% is widely used to determine MGMT promoter status as ‘methylated’ or ‘unmethylated’ (25-27). Although previous studies have shown that MGMT promoter methylation confers survival benefits in patients with glioma (16, 28-30), certain issues must be clarified. Studies have reported the presence of a ‘grey zone’ in regard to the methylation status and questioned whether the current dichotomizing method can reflect the actual methylation status of patients with GBM (10, 31, 32). In addition, some studies have suggested the possibility of a ‘hypermethylated’ MGMT methylation status, which may provide additional prognostic benefits to patients with GBM (10, 29, 33). Since individual CpG sites show methylation heterogeneity and may have different impacts on the prognostic value (32), low-methylated GBMs might comprise partly methylated tumours that do not completely fall into either the methylated or unmethylated categories. The extent of MGMT promoter methylation or protein expression levels may affect the distinct biological behaviour of hypermethylated and unmethylated tumour (29).

In this study, there was no significant difference in the OS and PFS of patients with hypermethylated and low-methylated GBM, even though the median OS and PFS tended to increase from the unmethylated to the hypermethylated group. However, the relatively small sample size might have influenced the statistical power in this study. Subsequent studies in larger cohorts are needed to confirm whether a status of hypermethylation of MGMT can confer additional survival benefits in patients with GBM. Furthermore, mechanistic details of MGMT methylation and ATRX loss must be elucidated in future studies.

Additionally, since this study strictly focused on GBM with wild-type IDH, further studies are needed to evaluate whether the present findings can be applied to other types of glioma.

In conclusion, we suggest a possible association between ATRX mutations and MGMT methylation status in patients with GBM with wild-type IDH. Although median OS and PFS tended to increase from those with an unmethylated status to those with a hyper-methylated status, there was no significant additional benefit distinguishing between hypermethylated and low-methylated groups, making further divisions of MGMT methylation status unnecessary. Subsequent studies with larger patient cohorts are needed to validate the findings of our study.

Acknowledgements

The Authors would like to thank Won Young Park and Yi Rang Kim for their dedicated efforts in MGMT promoter pyrosequencing.

Se Hoon Kim was supported by grants from the Brain Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT & Future Planning (Grant No. 2016M3C7A1913844). The funding source had no role in the design, practice, or analysis of this study.

Footnotes

  • Authors’ Contributions

    Se Hoon Kim and Jong Hee Chang conceived and designed the study. Moonsik Kim and Jihwan Yoo drafted the article. Jihwan Yoo analysed and interpreted the clinical data. Se Hoon Kim and Jong Hee Chang carefully reviewed and revised the article. All Authors read and approved the final article.

  • ↵* These Authors contributed equally to this work.

  • Conflicts of Interest

    The Authors declare no conflicts of interest.

  • Received October 23, 2021.
  • Revision received November 14, 2021.
  • Accepted November 18, 2021.

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Association of MGMT Gene Promoter Methylation With Clinicopathological Parameters in Patients With Wild-type IDH Glioblastoma
MOONSIK KIM, JIHWAN YOO, JONG HEE CHANG, SE HOON KIM
Anticancer Research Jan 2022, 42 (1) 335-341; DOI: 10.21873/anticanres.15490
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