O6-methylguanine DNA methyltransferase gene promoter methylation status in gliomas and its correlation with other molecular alterations: first Indian report with review of challenges for use in customized treatment.
BACKGROUND
O6-methylguanine methyltransferase (MGMT) promoter methylation in adult glioblastomas (glioblastoma multiforme) is considered a promising molecular alteration, predictive of better response to temozolomide therapy and longer overall survival.


OBJECTIVE
To look at the frequency of MGMT methylation in glial tumors of all grades and types, and correlate this alteration with loss of heterozygosity 1p/19q, TP53 gene mutations, epidermal growth factor receptor (EGFR) amplification, and isocitrate dehydrogenase 1 (IDH1) mutations.


METHODS
One hundred two gliomas of various grades and subtypes were assessed by methylation-specific polymerase chain reaction for MGMT promoter methylation status. The results were correlated with 1p/19q status, EGFR amplification, TP53, and IDH1 mutations.


RESULTS
There was an inverse correlation of MGMT promoter methylation frequency with tumor grade, observed in 79.4%, 70.8%, and 56.8% of grade II, grade III, and grade IV gliomas, respectively. The difference was statistically significant in grade II vs IV tumors (P=.036). The majority of cases with 1p/19q loss of heterozygosity also showed MGMT methylation, although the association was not significant. There was no significant correlation of MGMT status with IDH1 mutation. In astrocytic tumors, there was no correlation of MGMT methylation with TP53 mutation or EGFR amplification.


CONCLUSIONS
MGMT promoter methylation was observed in a considerable proportion of all grades and subtypes of gliomas, with no significant correlation with other known genetic alterations. On extensive literature review, in both low- and high-grade gliomas, wide variability of data on the frequency of MGMT methylation and its association with other molecular alterations from various centers was noted, mostly owing to technical causes. This raises questions regarding the capacity of this test for use as an objective and reproducible marker for customized treatment in individual cases.
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
Prerana
P
Jha
Vaishali
V
Suri
Ayushi
A
Jain
Mehar Chand
MC
Sharma
Pankaj
P
Pathak
Pankaj
P
Jha
Arti
A
Srivastava
Ashish
A
Suri
Deepak
D
Gupta
Kunzang
K
Chosdol
Parthoprasad
P
Chattopadhyay
Chitra
C
Sarkar
D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics*; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D015198:Designer Drugs; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D005910:Glioma / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D007194:India; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012189:Retrospective Studies; D000077204:Temozolomide; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
D018906:Antineoplastic Agents, Alkylating; D015198:Designer Drugs; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D003606:Dacarbazine; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D019853:O(6)-Methylguanine-DNA Methyltransferase; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077204:Temozolomide