How can you determine from FISH results if you have a chromosomal mutation or 'silencing'
of gene expression i.e. epigenetics?
Typically, the FISH test says gain or deletion...I take that to fall under mutation...is that correct? i.e. TP53 present (gain)but malfunctioning
However,
I recently read TP53 function can become compromised for three reasons:
1. 17p deletion where the TP53 gene is broken off and p53 protein production comes to a halt.
2. 17p mutation where the TP53 gene is present but messed up subtly and therefore the p53 protein it makes is also messed up and useless.
3. 17p silencing where the TP53 gene is willing and able to make the right p53 protein but it is covered up with gunk and cannot do its job.
If the FISH results say +TP53...does that mean there is a gain(mutation)...and how would you determine if it is a mutation vs an epigenetic silencing occuring? Or is that distinction possible based on FISH results?
It appears that the DAC agents (pabinostat/vorinostat/ romidepsin) are able to overcome the epigenetic silencing of TP53..and upregulate the activity.
Just curious, how the multiple myeloma experts are viewing this new therapeutic intervention.
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Re: FISH results TP53 Queries & DAC system
In cancer there two major genetic alterations (or epigenetic alterations).
The first involve "oncogenes"- normal genes that function in the growth and proliferation of cells. Typically, these are turned off when appropriate. However, in cancer they have acquired activating mutations or are produced at very high levels; thus producing proteins that are always on that drive cancer proliferation. The result: gas pedels stuck to the floor (think of the translocations associated with myeloma t(4:14); t(11:14), t(14:16)... or mutations in Ras or FGFR3).
Alternately, there are proteins that work normally by turning off growth or programming cells to die if they are not behaving appropriately. These are called "tumor suppressors." Loss of these by inactivating mutation, loss of the gene or part of the chromosome to which they belong, or epigenetic silencing is necessary for unfettered growth of cancer. In this case, the result is that the brakes have been cut (think: deletion of p53 or Rb or silencing of p15 or p16 by epigenetic means). P53 is a tumor suppressor gene, so loss of it or the chromosome containing it- the short arm of chromosome 17 (17p).
On FISH, a positive result means that the 17p is lost, not that there is an activating mutation. FISH should not be able to tell if it is epigenetically modified either as FISH is probing for the gene sequence and the gene product. Epigenetic control of gene expression is based on a lack of gene product, not loss of the gene.
The histone deacetylase (HDAC) inhibitors are a very exciting group of drugs in myeloma. However, their mechanism of action may not be as straightforward as the reactivation of epigenetically silenced tumor suppressors. These agents have been shown to help overcome Velcade refractoriness and are being studied in phase II and phase III studies in relapsed refractory patients. The success in Velcade refractory patients may, in fact, be a result of their indirect control of another proteolytic processing mechanism in myeloma cells.
Regardless, these are an exciting group of proteins in myeloma and other hematologic malignancies and bear careful watching.
The first involve "oncogenes"- normal genes that function in the growth and proliferation of cells. Typically, these are turned off when appropriate. However, in cancer they have acquired activating mutations or are produced at very high levels; thus producing proteins that are always on that drive cancer proliferation. The result: gas pedels stuck to the floor (think of the translocations associated with myeloma t(4:14); t(11:14), t(14:16)... or mutations in Ras or FGFR3).
Alternately, there are proteins that work normally by turning off growth or programming cells to die if they are not behaving appropriately. These are called "tumor suppressors." Loss of these by inactivating mutation, loss of the gene or part of the chromosome to which they belong, or epigenetic silencing is necessary for unfettered growth of cancer. In this case, the result is that the brakes have been cut (think: deletion of p53 or Rb or silencing of p15 or p16 by epigenetic means). P53 is a tumor suppressor gene, so loss of it or the chromosome containing it- the short arm of chromosome 17 (17p).
On FISH, a positive result means that the 17p is lost, not that there is an activating mutation. FISH should not be able to tell if it is epigenetically modified either as FISH is probing for the gene sequence and the gene product. Epigenetic control of gene expression is based on a lack of gene product, not loss of the gene.
The histone deacetylase (HDAC) inhibitors are a very exciting group of drugs in myeloma. However, their mechanism of action may not be as straightforward as the reactivation of epigenetically silenced tumor suppressors. These agents have been shown to help overcome Velcade refractoriness and are being studied in phase II and phase III studies in relapsed refractory patients. The success in Velcade refractory patients may, in fact, be a result of their indirect control of another proteolytic processing mechanism in myeloma cells.
Regardless, these are an exciting group of proteins in myeloma and other hematologic malignancies and bear careful watching.
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Dr. Ken Shain - Name: Ken Shain, M.D., Ph.D.
Beacon Medical Advisor
Re: FISH results TP53 Queries & DAC system
Hot diggity, Dr Shain!!
I absolutely love the medical/scientific expertise that provides an in-depth explanation as you did!!
You wrote:
"On FISH, a positive result means that the 17p is lost, not that there is an activating mutation. FISH should not be able to tell if it is epigenetically modified either as FISH is probing for the gene sequence and the gene product. Epigenetic control of gene expression is based on a lack of gene product, not loss of the gene."
Thanks for explaining FISH in detail as that enables me to correlate what they are saying in the literature regarding oncogenes and epigenetics relative to the FISH report, for the first time!!
I am still excited about the agents that work on the DAC system...it is very interesting that, you note it is now being postulated that the MOA of pabinostat could entail another proteolytic enzyme pathway.
After the the Wobe Mugos study and the 100 year old proteolytic enzyme theory Dr.Beard published in 1911.Seems everything new is old these days:
http://www.newspringpress.com/beard.html
After all can it really be that coincidental that the receptor sites on the protesome are being called trypsin and chymotrypsin like, or that Wobe Mugos now has orphan $tatu$?
Faith is all you have in the end.
Big pharma and whomever, the doc was that came up with that melphan conditioning (HA!) therapy needs to be treated like Jerry Sandusky.
I am looking forward to hearing exciting news from ASH in 2 weeks, as fhe field of multiple myeloma re-discovers...that the Nobel Prize winning Dr. Beard was right after all in 1902 when he first postulated the proteolytic enzyme theory.
I absolutely love the medical/scientific expertise that provides an in-depth explanation as you did!!
You wrote:
"On FISH, a positive result means that the 17p is lost, not that there is an activating mutation. FISH should not be able to tell if it is epigenetically modified either as FISH is probing for the gene sequence and the gene product. Epigenetic control of gene expression is based on a lack of gene product, not loss of the gene."
Thanks for explaining FISH in detail as that enables me to correlate what they are saying in the literature regarding oncogenes and epigenetics relative to the FISH report, for the first time!!
I am still excited about the agents that work on the DAC system...it is very interesting that, you note it is now being postulated that the MOA of pabinostat could entail another proteolytic enzyme pathway.
After the the Wobe Mugos study and the 100 year old proteolytic enzyme theory Dr.Beard published in 1911.Seems everything new is old these days:
http://www.newspringpress.com/beard.html
After all can it really be that coincidental that the receptor sites on the protesome are being called trypsin and chymotrypsin like, or that Wobe Mugos now has orphan $tatu$?
Faith is all you have in the end.
Big pharma and whomever, the doc was that came up with that melphan conditioning (HA!) therapy needs to be treated like Jerry Sandusky.
I am looking forward to hearing exciting news from ASH in 2 weeks, as fhe field of multiple myeloma re-discovers...that the Nobel Prize winning Dr. Beard was right after all in 1902 when he first postulated the proteolytic enzyme theory.
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suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
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