Abstract 23: The MGMT promoter methylation is correlated with gene mutation of IDH1 and 1p19q in glioma
Authors: Zhang Min , Ma Wanlong , Wu Weihua , Maher Albitar 
Published: May 2016

The purpose of this retrospective study includes the following; a summarization of the MGMT methylation status in glioma patients who were tested in our laboratory during 2013-2014, an investigation of the gene variation frequency with MGMT methylation, a better understanding of the dysfunction of signal pathway involved in glioma, and an evaluation of our brain tumor profile in clinical practice.

The Glioblastoma multiforme (GBM) is the most common primary brain tumor among adults and is still considered an incurable malignancy. Early diagnosis and treatment are very important. The mechanisms of glioma onset and progression remain largely unknown. Only a few significant correlations have been observed. One observation is the lower levels of O6-Methylguanine-DNA methyltransferase (MGMT) and a longer survival following treatment with alkylating agent-based chemotherapy. Current research also indicates that the most proliferation and apoptosis signaling pathways are actively involved in GBM transformation and metastasis, which include gene mutation in p53, pRB, PI3K–PTEN-Akt-mTOR, RAS/MAPK and STAT3 and ZIP4 signal pathway (1).

In this study, we included a total of 320 brain tumor samples. DNA extracted from FFPE tissues were tested by MGMT methylation PCR. 126 (39%) of the samples were methylated, the average level of methylation was 12.94%. 19 (15%) of methylation cases were below 10% and 60 (48%) of positive samples were hyper-methylated (positive rate over 50%). Interestingly, the result from our brain profile (by using Sanger Sequencing, FISH, and NGS) revealed that 1p19q co-deletion and the gene encodes isocitrate dehydrogenase 1 (IDH1) solid mutation at c. 395G&gt;A, p. R132H were highly co-expressed with MGMT promoter methylation. 53% of 1p19q co-deletion and 40% of IDH1 mutation were related with MGMT promoter methylation group, but only 27% of 1p19q and 6% IDH1 mutation with MGMT promoter un-methylation group. The Fisher exact test statistic value for both 1p19q and IDH1 mutation were significant higher in the methylated group than the un-methylated group (p &lt; 0.05). In MGMT methylated group, 77% of samples presented both 1p19q and IDH1 mutations. Also, the result from our brain panel test revealed a series of mutations in oncogenes which were closely related with gliomas.

Conclusion: 1) The most MGMT promoter methylation in gliomas are distributed in hyper methylation range. 2) The MGMT promoter methylation, 1p19q co-deletion, and IDH1 mutation are high frequency co-present in glioma patient. These three molecular markers are favorite outcome indicator. They are synergy to enhance anti-tumor effect. 3) TP53, PTEN, KIT, MET, ATRX, BCORL1, TET2, ASXL1, KDR mutations are involved gliomas. They are mostly distributed in MAKP or PI3K/AKT pathway which are important to regulate the cell proliferation and apoptosis, further affect tumor progressing. 4) The MGMT promoter methylation PCR and additional brain tumor profile supply an excellent platform for glioma. The result supports on subset diagnosis, specific treatment, and evaluation of the overall survival (OS) and development of new therapeutic approach.

Note: This abstract was not presented at the conference.

Citation Format: Min Zhang, Wanlong Ma, Weihua Wu, Albitar Maher. The MGMT promoter methylation is correlated with gene mutation of IDH1 and 1p19q in glioma. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 23.