DNA methylation and epigenetic inactivation of the O6-methylguanine methyltransferase (MGMT) gene induces MGMT deficiency, reducing the tumor cell's DNA repair capacity and increasing its susceptibility to alkylating chemotherapeutic agents. Consequently, adult patients whose tumors are deficient in MGMT have better outcomes with alkylator chemotherapy, and MGMT methylation has been proposed as a screening marker of deficient tumors. It has been demonstrated that both childhood pediatric brain tumors such as medulloblastoma patients and adult-onset brain tumors such as GBM exhibit the heterogeneity in the expression of MGMT due to the non-homogeneous pattern of epigenetic silencing. Does this fact reduce the reliance of the pathological examinations of the single biopsy to predict the susceptibility to TMZ???
http://neuro-oncology.oxfordjournals.org/content/6/3/200.long
http://www.nature.com/articles/srep22477
Some time ago I supported a tumor pharmacology project to measure and compare brain and breast tumors with respect to the activity of the MGMT (see below). As expectected, we found usually low (but still differing) levels of activity in brain tumors (mainly glioblastoma), but also a small percentage of about 5% of breast tumors with also a low activity of the MGMT enzyme. The advantage of direct measurments of enzymatic acitivity (in general, not only with respect to MGMT) about many genetic measurements is, that they give no real information about it.
Article O6-Methylguanine-DNA methyltransferase activity in breast an...
You are asking a very important question. We have to distinguish intra-biopsy from intra-tumoral MGMT promoter methylation heterogeneity. Based on current concepts, the higher the percentage of MGMT promoter hypermethylated cells within a tumor, the weaker the tumor's average DNA repair capacity and the better the initial average tumor response to temozolomide (nevertheless, during the course of treatment, selection and expansion of resistant, i.e. non-methylated, cells will occur). In case of of microsurgical gross total tumor resection, it may be possible to obtain a representative analysis of MGMT promoter methylation throughout the tumor which may adequately inform subsequent treatment decisions. In case of a single biopsy, however, there is a higher risk that the MGMT promoter methylation analysis may be non-representative of the entire tumor and therefore misleading. Thus, my answer to your question is „potentially yes“.
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