I was watching the webinar from Mayo and in the case of
anaplastic astrocytoma, mutant p53 was associated with a significant increase
in OS. If the p53 protein is a tumor suppressor then why is mutant p53
associated with longer OS?
Probably because of the association between mutant p53 and mutant IDH1. As a group, anaplastic astrocytoma without mutant p53 will be mostly IDH1 non-mutant, glioblastoma type tumors.
Thats a possibility but the graph was broken down based on three genetic findings and their survival. No association was made with other findings such as IDH1. That seems like an important variable to include. If I recall correctly (and I may not) the genetic findings were PTEN, which had the worst OS, P53 mutation which had a substantially better OS and, well I don't seem to recall the third one. Anyway, would be interesting to know if this was related to IDH1 or if that variable had been accounted for. What is the incidence if IDH1 mutant tumors with wild type p53? Is the OS greater than with mutant p53? That would be another very interesting piece of data. Especially since I wrestle with the chloroquine/p53/ zinc issue. If OS in IDH1 mutant tumors was essentially the same regardless of p53 status, then the issue would be rendered nothing more than mental gymnastics.
I plan on watching that presentation but haven't yet done so, so can't comment on the graph.
But basically IDH-mutant gliomas fall into 2 main categories: astrocytoma and oligodendroglioma. Nearly all (95-99%) IDH-mutant astrocytomas also have mutant p53. IDH-mutant oligodendrogliomas don't usually have p53 mutations, but instead have 1p/19q codeletion, TERT promoter mutation, and often FUBP1 and CIC mutation.
If we're talking about IDH-mutant astrocytoma, it would be difficult to properly compare survival in those with p53 mutations versus those without, since there are so very few cases that don't have p53 mutation.
I found the graph you mentioned, it's at 27:51 in the presentation.
It shows 3 curves: p53 mutant, PTEN mutant, and neither.
My interpretation of this graph is that the PTEN mutant, and neither groups would be mostly IDH wild-type, and would have survival similar to primary glioblastoma. The p53 mutant group would be predominantly IDH1 mutant. The graph is quite misleading as it makes it look like p53 mutation leads to favorable survival, when in fact it is most likely the predominance of IDH1 mutations in the mutant p53 group that is really determining the improved survival.
More to the point though, is that mutant p53 is definitely a tumor-promoter, and any therapy that either suppresses mutant p53 activity, or increases the activity of normal p53, would most likely lead to longer survival.
Immunohistochemistry (IHC) is a way to detect the presence of a protein, in this case the p53 protein. Increased staining for p53 is often found in tumors with mutant p53, since the mutant p53 proteins are stabilized and accumulate, while the normal p53 proteins are quickly broken down.
IDH1 mutant astrocytomas usually also have p53 mutations, but that would have to be confirmed with further testing, for example DNA sequencing of the TP53 gene.
Normal p53 proteins are usually quickly degraded. Mutant p53 proteins tend to resist breakdown and so tend to accumulate. There was a study published a couple years ago showing that at least 10% of tumor cells strongly positive for p53, or at least 40% of cells positive for any degree of staining for p53 (strong or weak) were predictive for p53 mutation. https://www.ncbi.nlm.nih.gov/pubmed/25040820
In the context of mutant IDH1 (is that the case?), you can assume there is a p53 mutation, as IDH1 and TP53 are usually co-mutated in astrocytomas.
Usually TP53 missense mutation lead to a detectable buildup of mutant p53 proteins. However, there are certain types of mutations, such as frameshift mutations, in which you would not get that same accumulation of mutant p53 proteins. So I'd say it's possible there is a TP53 mutation, but the more likely scenario is that there isn't one if there is no accumulation of p53.
Probably because of the association between mutant p53 and mutant IDH1. As a group, anaplastic astrocytoma without mutant p53 will be mostly IDH1 non-mutant, glioblastoma type tumors.
ReplyDeleteThats a possibility but the graph was broken down based on three genetic findings and their survival. No association was made with other findings such as IDH1. That seems like an important variable to include. If I recall correctly (and I may not) the genetic findings were PTEN, which had the worst OS, P53 mutation which had a substantially better OS and, well I don't seem to recall the third one. Anyway, would be interesting to know if this was related to IDH1 or if that variable had been accounted for. What is the incidence if IDH1 mutant tumors with wild type p53? Is the OS greater than with mutant p53? That would be another very interesting piece of data. Especially since I wrestle with the chloroquine/p53/ zinc issue. If OS in IDH1 mutant tumors was essentially the same regardless of p53 status, then the issue would be rendered nothing more than mental gymnastics.
ReplyDeleteI plan on watching that presentation but haven't yet done so, so can't comment on the graph.
ReplyDeleteBut basically IDH-mutant gliomas fall into 2 main categories: astrocytoma and oligodendroglioma. Nearly all (95-99%) IDH-mutant astrocytomas also have mutant p53. IDH-mutant oligodendrogliomas don't usually have p53 mutations, but instead have 1p/19q codeletion, TERT promoter mutation, and often FUBP1 and CIC mutation.
If we're talking about IDH-mutant astrocytoma, it would be difficult to properly compare survival in those with p53 mutations versus those without, since there are so very few cases that don't have p53 mutation.
I found the graph you mentioned, it's at 27:51 in the presentation.
ReplyDeleteIt shows 3 curves: p53 mutant, PTEN mutant, and neither.
My interpretation of this graph is that the PTEN mutant, and neither groups would be mostly IDH wild-type, and would have survival similar to primary glioblastoma. The p53 mutant group would be predominantly IDH1 mutant. The graph is quite misleading as it makes it look like p53 mutation leads to favorable survival, when in fact it is most likely the predominance of IDH1 mutations in the mutant p53 group that is really determining the improved survival.
More to the point though, is that mutant p53 is definitely a tumor-promoter, and any therapy that either suppresses mutant p53 activity, or increases the activity of normal p53, would most likely lead to longer survival.
ReplyDeleteI have a grade 2 astro, Idh positive. The path report says p53 protein status (IHC): Rare positive nuclei. What does this mean?
ReplyDeleteImmunohistochemistry (IHC) is a way to detect the presence of a protein, in this case the p53 protein. Increased staining for p53 is often found in tumors with mutant p53, since the mutant p53 proteins are stabilized and accumulate, while the normal p53 proteins are quickly broken down.
ReplyDeleteIDH1 mutant astrocytomas usually also have p53 mutations, but that would have to be confirmed with further testing, for example DNA sequencing of the TP53 gene.
P53: positive in approximately 30% of the tumour cells
ReplyDeleteDoes this mean 30% mutant p53 or 30% normal p53 proteins?
IDH1
Normal p53 proteins are usually quickly degraded. Mutant p53 proteins tend to resist breakdown and so tend to accumulate. There was a study published a couple years ago showing that at least 10% of tumor cells strongly positive for p53, or at least 40% of cells positive for any degree of staining for p53 (strong or weak) were predictive for p53 mutation.
Deletehttps://www.ncbi.nlm.nih.gov/pubmed/25040820
In the context of mutant IDH1 (is that the case?), you can assume there is a p53 mutation, as IDH1 and TP53 are usually co-mutated in astrocytomas.
The report says: IDH1 (R132H): immunonegative.
DeleteFollow up question on P53 - pathology report says accumulation not observed. IDH wild-type confirmed. Does this mean that there is no P53 mutation?
ReplyDeleteUsually TP53 missense mutation lead to a detectable buildup of mutant p53 proteins. However, there are certain types of mutations, such as frameshift mutations, in which you would not get that same accumulation of mutant p53 proteins. So I'd say it's possible there is a TP53 mutation, but the more likely scenario is that there isn't one if there is no accumulation of p53.
Delete