1.RASSF1A: One of the thing cancer cell do is to Methylate some genes in order to block its path to death.
it
appears this gene is a critical door to shut or disable. It not only
decrease the significance of RAS and MAPK in the pathogenesis of tumor
that harbor this mutation. It also remove blockage to proliferation by
desensitizing the cell to the effect of P53, Cyclins. Desensitize
the cell to Death Receptor 6 and its Fas connection. RASSF1a,
demethylation is a valid target in ovarian cancer.
2.HNF1B: " Hepatocyte Nuclear Factor 1α (HNF1α) is an atypical
homeodomain-containing transcription factor that transactivates
liver-specific genes including albumin, α-1-antitrypsin and α- and
β-fibrinogen. Biallelic inactivating mutations of HNF1A have
been frequently identified in hepatocellular adenomas (HCA), rare benign
liver tumors usually developed in women under oral contraceptives, and
in rare cases of hepatocellular carcinomas developed in non-cirrhotic
liver. HNF1α-mutated HCA (H-HCA) are characterized by a marked steatosis
and show activation of glycolysis, lipogenesis, translational machinery
and mTOR pathway. We studied the consequences of HNF1α silencing in
hepatic cell lines, HepG2 and Hep3B and we reproduced most of the
deregulations identified in H-HCA."
(Laura Pelletier et al)
This
gene is the gene of differentiation for liver formation, it has the
structure of a CBF (core binding Factor) therefore has a subunit binding
the DNA, therefore silencing that portion, and another subunit having
locations for enzymatic proteins or molecular structures that directly
assume various functions intended by the cell (formation of
Albumin, alpha Antitrypsine, and Beta Fibrinogen).
Interestingly enough,
Steatosis is a prominent feature here. This structure and gene may be of
interest in LIPOSARCOMA?
DOES ACTIVATION OF MTOR DEMONSTRATED HERE
OPEN THE DOOR TO THE USE OF MTOR IN LIPOSARCOMA?
Showing posts with label crrbcm. Show all posts
Showing posts with label crrbcm. Show all posts
Friday, April 5, 2013
Thursday, April 4, 2013
GENES IN OVARIAN CANCER: (part I)
The notion that there is a particular gene or genes for a specific cancer is attractive, but most of the time only reflects the scientists' tendency to attract the community interest on their findings. There is nothing wrong with that because their work needs recognition. Recent advances in cure and novel therapeutic approaches have occurred to convince the common of mortals that Researchers are hard at work. But by now we know that most standard genetic family abnormalities involve only 5-10% of cancers. That means that no one genetic abnormality stands to justify any specific cancer in-toto. The case of BRCA1 and 2 in Breast cancer.
Breast cancer survivor Women who participated in My talk in El Paso,TX were surprised to learn that 85% of women newly diagnosed with Breast cancer in the US were first in their family. Everybody was assuming that breast cancer happens because of family predisposition. This is clearly an underestimation of the heterogeneity of our genetic material. Don't understand me wrong, there are clear cases of family predispositions, however, we have an approximate 25,000 genes, something and somewhere a significant event can happen anytime. Also, one should know that there is primary and secondary amplification. In some cases it is hard to determine which came first (Chicken and egg dilemma ).
Another compounding factor complicating our interpretation in rare cases, is the notion that the cause of cancer can be located in the promoter gene which all of a sudden becomes difficult to methylate or suppress, causing secondary amplification of a gene or of its regulators.
When one wants to look at the genes involved in ovarian cancers, it is good to focus on particular genes (HNF1B) as clearly publicized, but we can't ignore the story of BRCAs, and other family syndromes which harbor Ovarian cancer as a component of the syndrome. Therapies that are being developed and being effective in Ovarian cancer (Anti MEK) are also pointing to relevant genes. The story of lung cancer with its ever expanding list of DRIVER MUTATIONS and the advent of MULTIPLEX gene screening is just another proof of the danger of claiming to have discovered THE GENE for a specific cancer!
GENES OF OVARIAN CANCER (to follow)
Breast cancer survivor Women who participated in My talk in El Paso,TX were surprised to learn that 85% of women newly diagnosed with Breast cancer in the US were first in their family. Everybody was assuming that breast cancer happens because of family predisposition. This is clearly an underestimation of the heterogeneity of our genetic material. Don't understand me wrong, there are clear cases of family predispositions, however, we have an approximate 25,000 genes, something and somewhere a significant event can happen anytime. Also, one should know that there is primary and secondary amplification. In some cases it is hard to determine which came first (Chicken and egg dilemma ).
Another compounding factor complicating our interpretation in rare cases, is the notion that the cause of cancer can be located in the promoter gene which all of a sudden becomes difficult to methylate or suppress, causing secondary amplification of a gene or of its regulators.
When one wants to look at the genes involved in ovarian cancers, it is good to focus on particular genes (HNF1B) as clearly publicized, but we can't ignore the story of BRCAs, and other family syndromes which harbor Ovarian cancer as a component of the syndrome. Therapies that are being developed and being effective in Ovarian cancer (Anti MEK) are also pointing to relevant genes. The story of lung cancer with its ever expanding list of DRIVER MUTATIONS and the advent of MULTIPLEX gene screening is just another proof of the danger of claiming to have discovered THE GENE for a specific cancer!
GENES OF OVARIAN CANCER (to follow)
Thursday, February 21, 2013
GENES IN UVEAL MELANOMA.
This one rings a bell with me because a good friend and respected professor, wife to an intensive care Doctor, died under our care before the discovery of Ipilimumab. And how well Ipilimumab fares in this particular case of melanoma is still to be closely reviewed (DTIC was not trusted enough). At the time, the patient who had liver metastasis ended up getting an Abraxane based combination.
Researchers from Washington University have now published that the SF3B1 gene could predict a better outcome in patients with Uveal Melanoma since it is linked to far lower metastasis rate and young individuals.
3 additional genes were cited also: BAP1, GNAQ, GNA11,
1. SF3B1
===== Splicing factor 3B subunit 1
Being a splicing factor puts this gene right there in the differentiating gene as we discussed earlier. Meaning the gene pushes differentiation further up which in cellular biology has been proven to normal life and submission to normal programmed death. The ATRA story used in APL is proof in the pudding.
SB3F1 is a good prognosis gene globally. In MDS, it is known to be associated with early MDS, particularly the MDS with ring Sideroblast. This fact is noticeable and warrants a speculative comment. That is when you talk of Sideroblast, you incriminate disturbances in Iron Metabolism in or around the Mitochondria. What does create similar iron disturbance? Well, Inflammatory processes do. This is confirmed by the link of Splicing Factors to production of Inflammatory proteins and therefore participation in connective tissue disease. Remember, early MDS can respond to Immune based therapeutic interventions. So, SB3F1 seems to be an Early event. To affect differentiation, it must lead to proteins that interact with later Splicing factors and impose a trend away from Apoptosis and migration. The literature suggests that it is an "evolutionary", that it has an impact on cellular evolution. The SB3F1 has been seen also in Breast cancer with similar prognosis indications.
The notion that one of the proteins resulting from various splicing factors could be Autoantigenic brings another dimension to bear! That an abnormality at SB3F1 could in effect produce Autoantigen making the cell susceptible to Autoimmune death, another way that would limit its chances of spreading. Remember, Melanoma is often susceptible to Interferon and now T cell CTLA-4 related agents (such as Ipilimumab).
SB3F1, an early Mutation, influencing other late splicers and therefore "evolutionary", and rising autoimmunity!
(In MDS, SB3F1 is also associated with high Hb, Platelet counts, all the good stuff of better prognosis). It has been noted in CLL, MDS and Breast cancer, and now Uveal Melanoma.
Presence of TET2, an angel of proliferation, will stop the good prognosis acting of SB3F1. And so will the presence of Mutations in P53, EZH, ETV6, RUNX-1, and ASXL! (check it out!) it's all in the literature...
2. BAP-1
--------------
Members of the polycomb-group proteins (PcG) of highly conserved transcriptional repressors required for long-term silencing of genes that regulate cell fate determination, stem cell pluripotency, and other developmental processes.[3]" (wikepedia
In cancer, BAP1 can function both as a Tumor suppressor and as a Metastasis suppressor.
BAP1 mutations were identified in a small number of breast and lung cancer cell lines,[1] but BAP1 was first shown to act as a tumor suppressor in cultured cells, where its deubiquitinase (UCH) domain and Nuclear localization sequences were required for BAP1 to suppress cell growth.[9] In 2010, Exome sequencing identified inactivating mutations in BAP1 in 47% of Uveal melanomas, and BAP1 mutation was strongly associated with metastasis.[10] These mutations included multiple Nonsense mutations and splice site mutations throughout the gene. missense mutations were only found within the UCH and ULD domains, further supporting the requirement for BAP1 catalytic function. This study also identified a Germline mutation in one of the uveal melanoma patients, suggesting that, besides being a Metastasis suppressor, BAP1 could predispose certain people to more aggressive uveal melanoma tumors. Shortly thereafter, BAP1 mutations were identified in aggressive Mesotheliomas with similar mutations as seen in melanomas,[11] and have also been reported in renal cell carcinomas.[12]
Two studies used Genome sequencing independently to identify Germline mutations in BAP1 in families with Genetic predispositions to mesothelioma[13] and melanocytic skin tumors[14] Further studies have identified germline BAP1 mutations associated with other cancers.[15] These studies suggest that germline mutation of BAP1 results in a Tumor Predisposition Syndrome linking BAP1 to many more cancers. (wikipedia)
In lung cancer, it is associated with no lymph node involvement and therefore of Good prognosis.
BRCA-1 Associated Protein-1 could be associated with BRAF, and 15% of clear cell Renal cancers.
This one rings a bell with me because a good friend and respected professor, wife to an intensive care Doctor, died under our care before the discovery of Ipilimumab. And how well Ipilimumab fares in this particular case of melanoma is still to be closely reviewed (DTIC was not trusted enough). At the time, the patient who had liver metastasis ended up getting an Abraxane based combination.
Researchers from Washington University have now published that the SF3B1 gene could predict a better outcome in patients with Uveal Melanoma since it is linked to far lower metastasis rate and young individuals.
3 additional genes were cited also: BAP1, GNAQ, GNA11,
1. SF3B1
===== Splicing factor 3B subunit 1
Being a splicing factor puts this gene right there in the differentiating gene as we discussed earlier. Meaning the gene pushes differentiation further up which in cellular biology has been proven to normal life and submission to normal programmed death. The ATRA story used in APL is proof in the pudding.
SB3F1 is a good prognosis gene globally. In MDS, it is known to be associated with early MDS, particularly the MDS with ring Sideroblast. This fact is noticeable and warrants a speculative comment. That is when you talk of Sideroblast, you incriminate disturbances in Iron Metabolism in or around the Mitochondria. What does create similar iron disturbance? Well, Inflammatory processes do. This is confirmed by the link of Splicing Factors to production of Inflammatory proteins and therefore participation in connective tissue disease. Remember, early MDS can respond to Immune based therapeutic interventions. So, SB3F1 seems to be an Early event. To affect differentiation, it must lead to proteins that interact with later Splicing factors and impose a trend away from Apoptosis and migration. The literature suggests that it is an "evolutionary", that it has an impact on cellular evolution. The SB3F1 has been seen also in Breast cancer with similar prognosis indications.
The notion that one of the proteins resulting from various splicing factors could be Autoantigenic brings another dimension to bear! That an abnormality at SB3F1 could in effect produce Autoantigen making the cell susceptible to Autoimmune death, another way that would limit its chances of spreading. Remember, Melanoma is often susceptible to Interferon and now T cell CTLA-4 related agents (such as Ipilimumab).
SB3F1, an early Mutation, influencing other late splicers and therefore "evolutionary", and rising autoimmunity!
(In MDS, SB3F1 is also associated with high Hb, Platelet counts, all the good stuff of better prognosis). It has been noted in CLL, MDS and Breast cancer, and now Uveal Melanoma.
Presence of TET2, an angel of proliferation, will stop the good prognosis acting of SB3F1. And so will the presence of Mutations in P53, EZH, ETV6, RUNX-1, and ASXL! (check it out!) it's all in the literature...
2. BAP-1
--------------
Members of the polycomb-group proteins (PcG) of highly conserved transcriptional repressors required for long-term silencing of genes that regulate cell fate determination, stem cell pluripotency, and other developmental processes.[3]" (wikepedia
In cancer, BAP1 can function both as a Tumor suppressor and as a Metastasis suppressor.
BAP1 mutations were identified in a small number of breast and lung cancer cell lines,[1] but BAP1 was first shown to act as a tumor suppressor in cultured cells, where its deubiquitinase (UCH) domain and Nuclear localization sequences were required for BAP1 to suppress cell growth.[9] In 2010, Exome sequencing identified inactivating mutations in BAP1 in 47% of Uveal melanomas, and BAP1 mutation was strongly associated with metastasis.[10] These mutations included multiple Nonsense mutations and splice site mutations throughout the gene. missense mutations were only found within the UCH and ULD domains, further supporting the requirement for BAP1 catalytic function. This study also identified a Germline mutation in one of the uveal melanoma patients, suggesting that, besides being a Metastasis suppressor, BAP1 could predispose certain people to more aggressive uveal melanoma tumors. Shortly thereafter, BAP1 mutations were identified in aggressive Mesotheliomas with similar mutations as seen in melanomas,[11] and have also been reported in renal cell carcinomas.[12]
Two studies used Genome sequencing independently to identify Germline mutations in BAP1 in families with Genetic predispositions to mesothelioma[13] and melanocytic skin tumors[14] Further studies have identified germline BAP1 mutations associated with other cancers.[15] These studies suggest that germline mutation of BAP1 results in a Tumor Predisposition Syndrome linking BAP1 to many more cancers. (wikipedia)
In lung cancer, it is associated with no lymph node involvement and therefore of Good prognosis.
BRCA-1 Associated Protein-1 could be associated with BRAF, and 15% of clear cell Renal cancers.
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