MGMT and Methylation

Methylation of MGMT
Many people are wondering about MGMT and what it means for brain tumor treatment.
MGMT (O-6-methlylguaninine-DNA methlytransferase) is a DNA repair protein which transfers a methyl group from guanine to itself. Methylation of the MGMT promoter within tumor cells prevents expression of MGMT, limiting DNA repair ability of the tumor cell. Methylation of MGMT promoter makes tumor cells more responsive to alkylating agents such as temozolomide, CCNU and BCNU. MGMT methylation is a genetic marker obtained from the tumor biopsy. In gliomas, MGMT promoter methylation is shows longer survival when receiving either radiation or chemotherapy.
MGMT methylation presence or absence is not presently used or approved as part of the treatment. Patients with glioblastoma, or high grade gliomas will usually receive temozolomide regardless of their MGMT methylation status. In the next step towards personalized medicine, MGMT promoter methylation testing will be used as a marker for patient selection within clinical trials.
Mary Lovely, PhD, RN, CNRN

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Thank you for elaborating on MGMT methylation. I have an interesting situation. My husband's MGMT was negative after his first resection, but after his second resection it was positive. Could you please explain this, if possible? My husband is still on Temodar even though it didn't work the first time. I'm assuming that it didn't work the first time because he was MGMT negative. His NO still has him on Temodar and now Avastin. He has also had cancer vaccine immunotherapy. Our NO told us there's no sense in worrying about biomarkers because GBM changes so much. He said, "that's why it's called multiforme". I disagree with him, but he's the director of a major cancer institute so I'm assuming he is correct.

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I think I previously misunderstood how this was characterized. I must have had it backwards.

If someone is "positive for MGMT methylation", than they respond better to chemotherapy?

Thanks

Erica

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One thing I have learned about gliomas is that many systems are involved in why tumors grow. MGMT methylation is just one of the many systems that may or may not have an effect. Scientists have been able to identify the methylation, and they are working on the others. The more we know of the all of the systems, the better information we have for treating the tumor. We can fight it in several ways. It is complicated because Glioblastomas can be made up of many different genes, and studies have shown that they change over time.

The question about methylated MGMT. Yes, the methylated MGMT is more responsive to chemotherapy.

Mary Lovely PhD, RN, CNRN

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Thank you, I appreciate the clarification.

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Dingo: I read from dr. Ben William's report regarding MGMT, it goes as "More specifically, there is an enzyme produced by the “MGMT” gene that allows the damaged tumor cells to repair themselves, with the result that both radiation and chemotherapy are less effective. Patients whose MGMT gene is inactivated (which occurs in 35-45% of patients) have a significantly greater chance of responding to temodar than those for whom the gene is still functional (4). For patients with an inactive gene, two-year survival was 23% for those receiving radiation only, compared to 46% for those who received radiation and temodar together. For those with an active MGMT gene the corresponding numbers were 2% and 14%. This implies that patients should have tumor tissue taken at the time of surgery tested for the status of the MGMT gene."

So, if I read right, the positive of MGMT, means it will respond LESS to chemo and Radiation, not the other way around. I hate to break this to you dingo, but My dad is also MGMT+....

Stay strong, Love

Viv

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Maybe I was wrong... can anyone help me ? I pray for my dad, hope he will respond to TMZ....

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@ vivienjun

My initial interpretation was the same was yours from reading David's pathology report and Ben Wiliam's report, but after reading the above post I did additional research. Methylated MGMT apparently means the MGMT gene is diminished. I am not sure if there is a difference between "positive for MGMT methylation" and "MGMT positive".

http://www.translational-medicine.com/content/10/1/36

"...the 24-months overall survival curves for primary glioblastoma patients receiving standard radiotherapy and at least concomitant TMZ displayed a trend towards better survival in the patient group with methylated MGMT promoter than in the patient group with unmethylated MGMT promoter..."

http://labs.unchealthcare.org/forms/mgmt_glioblastoma.pdf

"...MGMT is a DNA repair enzyme that reverses alkylation of guanine by transferring the alkyl group to the active site of the enzyme. Diminished MGMT expression due to methylation of CpG sites in the 5’ portion of the MGMT gene allows accumulation of alkylguanine DNA which, following incorrect base pairing with thymine, triggers DNA damage signaling and cell death. MGMT methylation is associated with increased sensitivity of glioblastoma to alkylating agents such as BCNU (carmustine), and it also correlates with prolonged progression-free survival in glioma patients treated with temozolamide."

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Thanks dingo.

On my dad's test report, it only shows only MGMT+, does it mean he has better chance to react to TMZ? Is your + or -? Or we need to have another test done to determine if chemo would work well? I guess if the test wasn't done during the surgeon, we have no way to know now right?

Stay strong, Love

Viv

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Perhaps, there is more than one truth...

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@ vivienjun

I am not sure. David's report just states "positive for MGMT methylation".

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@dr Lovely,

Could you help educate us. On my dad's report, it didn't mention anything about methylation, but only MGMT (+). Does that mean he is less response to TMZ?

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Dear Vivienjun,
I have noticed that statement MGMT (+) and have hesitated to respond because it is an abbreviated name for a result. Ask your husband's doctor to translate what it means so you have the correct answer. Some labs may be stating results differently from others. Please feel free to share your results with the rest of us on Connections.
Sincerely,
Mary Lovely, PhD, RN, CNRN

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