Quite a bit of interest has resulted from a recent study performed by investigators at Mayo Clinic and UCSF with respect to various molecular categories of glioblastoma. http://www.ncbi.nlm.nih.gov/pubmed/26061753 http://www.nejm.org/doi/full/10.1056/NEJMoa1407279
For the non-aficionado, these studies are very complex and confusing. If you have a PhD in molecular genetics you might understand it. I will attempt to try to explain some of the esoteric findings presented in this paper and to facilitate an understanding of how they can impact patients with malignant brain tumors on a day-to-day basis.
First of all, a bit of background. Until about 10 years ago, malignant gliomas were graded primarily just on their histological features, i.e., oligodendrogliomas and astrocytomas were locked into a category called glioma. Most of these, in terms of sheer numbers were astrocytomas. In children and young adults, you can find grade 1 astrocytomas which are a distinct entity and not what we’re talking about here. In young adults you can see grade 2 and grade 3 astrocytomas and occasionally grade 4 astrocytomas which are also called glioblastoma multiforme or GBM.
Until about 10 years ago we knew that GBM’s either presented as slowly evolving tumors from a lower grade called secondary GBM or as tumors that arose out of the blue suddenly, primarily in older patients, and these were called primary GBM. These 2 types of GBM were thought to be distinct, and it turns out that genetically they probably are different beasts. Around 10 years ago, analysis of Gene expression from hundreds of tumors determined that if you took all GBM, some of them had features that were more consistent with the biology of neurons, and some had features which were more consistent with a type of cell called mesenchymal cell which is more highly invasive and aggressive. There were some other categories as well. Long story made short, most of the primary GBM’s were either classical or mesenchymal, and many of the slowly evolving ones were pro neuronal. The ones that were prone neuronal or neuronal, seem to do better in terms of patient’s survival.
The current study looks at the gene mutations seen in the grade 2, grade 3 and grade 4 (GBM) tumors. Most of the primary GBM’s that show up out of the blue in older patients, are associated with a mutation called TERT (telomerase reverse transcriptase). This mutation is involved in maintaining part of a chromosome called the telomere, which has often been described as the little thing at the end of your shoelace that allows it to prevent from being unfrazzled. As long as this little thing is there, the chromosomes can keep dividing, but when it wears out over multiple cell divisions the cell is no longer able to divide. Cancer, having an endless supply of these little things on the end of the shoelaces or chromosomes allows the chromosomes to keep dividing forever, which is bad. Therefore, having the TERT mutation is bad.
Some other mutations that are more frequently seen in the grade 2 and grade 3 tumors include IDH1 (Isocitrate dehydrogenase 1) and 1P 19 Q. IDH1 mutation has been found independently to be associated with lower grade tumors and may be one of the first mutations seen in those slowly evolving secondary GBM’s. In general this portends a good outcome. Similarly 1P 19 Q is associated more frequently with lower grade tumors and specifically some of the oligodendroglioma tumors. Tumors that have 1P 19 Q deletions often respond better to chemotherapy drugs such as PCV and temozolomide. The researchers found that about 30% of patients with grade 2 and grade 3 astrocytomas were so-called “triple positive”, meaning that they had IDH1 mutations, 1P 19 Q deletions, and TERT mutation. In terms of prognosis, grade 2 and grade 3 astrocytoma patients that had triple positivity, TERT and IDH1, or IDH1 mutation alone had the best prognosis. If you have a grade 2 or grade 3 astrocytoma and you have TERT mutation without the other ones, you have a much worse prognosis. Also, as mentioned, TERT mutation alone without the other ones is seen in most of the primary glioblastoma’s that present out of the blue in older patients.
So what does this mean for the typical patient and family member of patients with astrocytomas? Well, it’s pretty likely that most community hospitals will not be testing for these mutations, so you’ll probably never know. If you did find out that you have a low-grade tumor that has TRT mutation only, unfortunately you are in a poor prognosis category.
These research findings will primarily be helpful to researchers and possibly clinicians in order to predict outcomes in patients. As far as I can tell there is no immediate clinical, treatment impact from this research. I should note however that there is exciting work being done with the notion that we may be able to vaccinate against the IDH1 mutation proteins in patients that have that mutation, and this may eventually lead to an immunotherapy and that subset of patients, primarily the low-grade glioma patients, who do have the IDH1 mutations.
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