I've spent some time on the sister site, AstrocytomaOptions, but I'm still not quite sure of the significance of these two markers.
My wife doesn't appear to have either of these mutations and I'm not sure if that's a good or bad thing, or is it merely a status. Does someone that doesn't have these mutations change their cocktails, and if so, in what meaningful way?
Thoughts?
IDH1 mutation (specifically IDH1 R132H) is the most common mutation associated with lower grade (2 and 3) gliomas (astrocytoma and oligodendroglioma). It is also found in secondary GBM evolving from lower grade gliomas, and rarely in GBM.
ReplyDeleteWhether it's a good or bad thing is relative - it is most likely the earliest genetic alteration in these tumors, that is to say, without this mutation there would likely be no tumor in these cases, so in that sense it is bad. On the other hand, these tumors tend to be more sensitive to standard treatments (chemo and radiation), are more usually in a frontal, surgically accessible location with more frequent complete resection, and also have metabolic handicaps, which perhaps slows their growth from what it otherwise would be. In this sense an IDH1-mutant glioma is a more favorable diagnosis.
But when speaking of GBM, IDH-mutant cases are in the minority, and most preclinical and clinical studies have been done with IDH-non-mutant GBM. Virtually all lab studies to date, with a few exceptions, have been carried out with IDH non-mutant GBM samples (IDH1 mutations were first discovered in glioma in 2008, relatively recently, and it has proven very difficult to culture these cells in the lab long-term, or generate in vivo xenografts).
So the actual situation is that most of the data that exists for glioma/GBM applies to IDH non-mutant types (IDH "wild-type"). I take an interest in IDH mutant types for personal reasons (friends with this diagnosis).
IDH1-mutants are more frequently MGMT-methylated, while non-IDH-mutant GBM is more frequently MGMT-unmethylated, meaning that chemosensitizers are more important for the latter. This is one important difference. IDH-non-mutant GBM is also commonly driven by EGFR alterations and the PI3K-> mTOR pathway, which is not so much the case with IDH-mutant lower grade gliomas. The list of differences could go on.
Thank you for this - exactly what I was hoping to understand. Strange as my wife is MGMT-methylated, non-IDH, and also her GBM seems to have arisen from a Grade III. She has a strange version of GBM and I don't know if this is a good or bad thing either.
DeleteIt's not so much a strange version as it is a version more common in pediatric cases: the peak age for her type of tumor is age 14.
DeleteI think one of the key strategies in her case is figuring out how to target the H3F3A G34 mutation. I was just about to re-read this study to refresh my memory:
ReplyDeletehttp://www.ncbi.nlm.nih.gov/pubmed/23539269
MYCN seems to be an important target for this type according to the above paper. MYCN is commonly associated with neuroblastoma, which is sometimes treated with 13-cis retinoic acid as maintenance therapy:
http://www.cancer.org/cancer/neuroblastoma/detailedguide/neuroblastoma-treating-retinoid-therapy
http://www.ncbi.nlm.nih.gov/pubmed/17554788
I've not seen retinoic acid tried as a therapy for H3F3A G34 mutant glioma, but this is an interesting lead to follow.
However, I would be careful of combining retinoids with epigenetic drugs (vorinostat, 5-azacytidine, valproic acid) because of this recently published paper:
ReplyDeletehttp://www.ncbi.nlm.nih.gov/pubmed/27069124
"Combined Treatment of ATRA with Epigenetic Drugs Increases Aggressiveness of Glioma Xenografts."
Glad you posted this - we're back on VPA as she can't tolerate Keppra. Thanks, as always, for the wealth of info!
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