Retrospective study on MGMT methylation status and its clinical significance in gliomas

doi:10.19401/j.cnki.1007-3639.2023.08.003

Abstract

Abstract:

Background and purpose: Glioma is a common malignant tumor of central nervous system with poor prognosis. Postoperative concurrent chemoradiotherapy with temozolomide (TMZ) is the main treatment for glioma. The methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter can predict the sensitivity of glioma patients to TMZ treatment, however its relationship with clinical pathology and how to better predict treatment and prognosis still need further research. The purpose of this study was to analyze the status of MGMT promoter methylation (MGMTmet) in gliomas and its correlation with clinical pathological features and other common molecular abnormalities, and to explore the value of combined analysis of MGMTmet and other molecular abnormalities in predicting the prognosis of glioma and the efficacy of TMZ treatment. Methods: We retrospectively collected clinical and pathological data from 205 glioma patients diagnosed by the Department of Pathology, Fudan University Shanghai Cancer Center from July 2019 to September 2022. Real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR) was used to detect MGMTmet status. Sanger sequencing was used to detect the mutation of isocitrate dehydrogenase 1 and 2 (IDH1/2) and telomerase reverse transcriptase (TERT) genes. Fluorescence in situ hybridization (FISH) was used to detect the deletion of the short arm of chromosome 1 and the long arm of chromosome 19 (1p19q). Results: Among 205 patients, the incidence of MGMTmet was higher in female patients than in male patients. Compared to glioblastoma (47.3%), astrocytoma (74.1%) and oligodendroglioma (100.0%) were more prone to methylation of the MGMT gene promoter (P<0.05). In MGMTmet group, IDH1 mutation rate and 1p19q co-deletion rate were significantly increased, and methylation of MGMT promoter was correlated with IDH1 mutation and 1p19q co-deletion (P<0.05). Patients with MGMTmet, age less than 55 years, oligodendroglioma, and World Health Organization (WHO) grade 1-3 all showed longer overall survival (OS), and the difference is statistically significant (P<0.05). Compared with individual influencing factors, dual/triple gene combination analysis (MGMTmet/IDH1 mutation or MGMTmet/1p19q co-deletion or MGMTmet/IDH1 mutation/1p19q co-deletion) had better effect for predicting the patient prognosis (P<0.05), with the latter two being independent prognostic factors. Among TMZ treated patients, MGMTmet (MGMTmet/TMZ+) patients had a better prognosis than other groups. If the patients had combined IDH1 mutations, the prognosis of the patients was further improved (P<0.05). Conclusion: MGMTmet is more common in women and patients with oligodendroglioma. It is positively correlated with IDH1 mutation and 1p19q co-deletion. Patients with MGMTmet are associated with better TMZ treatment efficacy and prognosis, and MGMTmet combined with IDH mutations and 1p19q co-deletion analysis have better TMZ treatment efficacy and prognostic implications.

Key words: Glioma, O6 methylguanine DNA methyltransferase, Double/triple gene conjoint analysis, Prognosis, Temozolomide

CLC Number:

R739.41

JIANG Lin, LIU Qiying, JIA Liqing, ZHANG Jing, CHANG Heng, XUE Tian, REN Min, BAI Qianming, ZHU Xiaoli, ZHOU Xiaoyan. Retrospective study on MGMT methylation status and its clinical significance in gliomas[J]. China Oncology, 2023, 33(8): 740-750.

Figures/Tables 6

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References 31

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Characteristic	Case n	MGMT promotor methylation	χ²	P value
Gender			4.037	0.045
Male	125	70
Female	80	56
Age/year			2.333	0.127
<55	120	79
≥55	85	47
Tumor location			7.026	0.071
Cerebellum brain stem	6	3
Temporo-occipital lobe	47	25
Frontal lobe	69	51
Others	83	47
Tumor histological type			42.080	<0.001
Glioblastoma	93	44
Oligodendroglioma	33	33
Astrocytoma	58	43
Others	21	6
WHO grade			26.730	<0.001
4	120	57
3	36	33
1+2	49	36

Molecular characteristics	MGMTmet (n=127)	MGMTunmet (n=78)	χ²	P value
IDH1mut			35.248	<0.001
-	53 (41.7)	60 (76.9)
+	67 (52.8)	9 (11.5)
NA	7 (5.5)	9 (11.5)
IDH2mut			4.391	0.111
-	111 (87.4)	69 (88.5)
+	6 (4.7)	0 (0.0)
NA	10 (7.9)	9 (11.5)
1p19q co-deletion			15.588	<0.001
-	42 (33.1)	28 (35.9)
+	36 (28.3)	5 (6.4)
NA	49 (38.6)	45 (57.7)
TERT mutation			1.412	0.494
-	38 (29.9)	20 (25.6)
+	86 (67.7)	54 (69.2)
NA	3 (2.4)	4 (5.1)

Item	Case n	OS $ (\overline{x}\pm s)$ t/month	χ²	P value
Gender			2.406	0.121
Male	125	15.18±18.99
Female	80	15.63±13.26
Age/year			24.683	< 0.001
<55	120	18.10±20.07
≥55	85	11.48±10.04
Tumor location			1.838	0.607
Cerebellum brain stem	6	11.50±10.15
Temporo-occipital lobe	47	15.26±12.77
Frontal lobe	69	18.94±21.99
Others	83	12.71±14.04
Tumor histological type			24.437	< 0.001
Glioblastoma	93	11.74±10.90
Oligodendroglioma	33	21.61±26.19
Astrocytoma	58	17.79±18.26
Others	21	14.81±13.91
WHO grade			29.622	< 0.001
4	120	13.14±12.34
3	36	22.03±25.59
1+2	49	15.88±17.88
MGMT methylation			9.629	0.002
Negative	78	13.71±13.67
Positive	127	16.37±18.66
IDH1mut			12.563	0.002
-	113	13.54±15.80
+	76	18.64±18.72
NA	16	12.56±14.29
IDH2mut			3.226	0.199
-	180	14.70±15.14
+	6	42.17±43.90
NA	19	13.11±13.83
1p19q co-deletion			11.554	0.003
-	70	15.83±17.05
+	41	20.54±23.91
NA	94	12.74±12.23
TERT mutation			2.859	0.239
-	58	16.98±20.91
+	140	14.84±15.38
NA	7	12.14±9.34
MGMT/IDH1			18.528	0.001
Met/mut	67	18.72±19.23
Met/wt	53	14.70±18.58
Unmet/mut	9	18.11±15.20
Unmet/wt	60	12.52±12.93
NA	16	12.56±14.29
MGMT /1p19q			23.739	< 0.001
Met/co-del	36	21.81±25.08
Met/non co-del	42	16.50±18.66
Unmet/co-del	5	11.40±9.69
Unmet/non co-del	28	14.82±14.58
NA	94	12.74±12.23
MGMT/IDH1/1p19q			14.553	0.002
Met/mut/co-del	26	18.62±19.02
1 or 2 positive	64	18.77±21.79
Unmet/wt/non co-del	18	13.17±14.82
NA	97	12.64±12.12

Prognostic factor	B	SE	Wald	P value	HR	95% CI
Age	1.011	0.388	6.792	0.009	2.749	1.285-5.882
Tumor histological type	-0.057	0.224	0.064	0.801	0.945	0.609-1.467
WHO grade	-1.275	0.534	5.697	0.017	0.279	0.098-0.796
MGMT status	0.188	0.675	0.077	0.781	1.206	0.321-4.531
IDH1 status	-0.019	0.377	0.003	0.959	0.981	0.469-2.052
1p19q codel	0.378	0.308	1.500	0.221	1.459	0.797-2.67
MGMT/IDH1status	0.082	0.263	0.096	0.757	1.085	0.648-1.818
MGMT/1p19q status	0.989	0.400	6.127	0.013	2.689	1.229-5.883
MGMT/IDH1/1p19q status	-1.257	0.597	4.426	0.035	0.285	0.088-0.918