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Msg  16 of 24  at  1/22/2022 6:47:35 AM  by

biotech2k

The following message was updated on 1/22/2022 2:48:19 PM.

Genetics of Cancer

   
 
DNA Damage Repair Pathways 
 
 
On average, the DNA polymerase that copies the DNA during the S phase of the cell cycle makes a mistake once in every 1 billion base pairs. That means each cell makes about 1 mistake each time it replicates.
 
Most of these errors are caught by the cell machinery that checks the DNA. Every once in a while, a mistake happens.
 
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There is a set of proteins and enzymes that are designed to find and repair different kinds of DNA damage. If it is just a single base error, then the DNA Damage Repair (DDR) proteins will undergo Base Excision Repair (BER).
 
This is where the specific base is removed and fixed. It can be a deamination of a cytosine, a depurination or even a alkylation of a base. 
 
If two bases have an issue like they become bound to each other called a pyrimidine dimer, then the Nucleotide Excision Repair (NER) kicks in. The binding together of two bases is a common type of damage from things like chemicals and UV light.
 
When that happens the NER repair will remove and replace a section of the DNA strand. NER will also fix what is called bulky groups in the DNA. These are large multi ringed groups from carcinogens and chemicals. They get into the DNA and need to be removed by NER.
 
When both strands of DNA get broken in what is called a Double Stranded Break (DSB), other sets of repair proteins will go to work. The process of Non Homologous End Joining is the most inaccurate way for DNA repair.
 
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This process basically takes two ends of DNA and just glues them back together. It doesn't even care if they belong together. A second method can be used for DSB with Homology Directed Repair. This will take the matching chromosome and use it as a template to repair the break.
 
When it is only 1 strand of DNA that gets broken, the DNA will undergo Single Strand Break Repair. This is the pathway were the famous BRCA gene exists. It takes the good strand of DNA and uses it as template to repair the broken strand.
 
The DDR machinery is designed to find and fix the damaged DNA. When something gets too bad for these mechanisms, then the cell will undergo programmed cell death.
 
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Mutations in the DDR repair mechanisms will lead to genetic instability which will allow the cell to accumulate more mutations at a faster rate.
 
There is a new approach to targeting cancer called Synthetic Lethality. This uses the defects in the DDR repair pathways that allow cancer to gain faster mutations against the cancer to push it into such instability that it initiates programmed cell death called Apoptosis.
 
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This is like the bar stool approach. If you have a four legged bar stool and a leg breaks, it might have only three legs, but it will most likely still work. If you kick out another leg, then it becomes unstable and collapses.
 
The process of Synthetic Lethality looks for mutated DDR pathways that promote cancer mutations. Then it looks for another point in the DDR pathways that can be knocked out to cause the cell to become so unstable it undergoes cell death.
 
 
Chromosomal Abnormalities
 
The normal human cell has two copies of each chromosome. One chromosome comes from mom and the other from dad. This gives us 23 pairs of chromosomes. We call this diploid meaning we have two copies of each chromosome.
 
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When the cell goes through the cell cycle, it copies all its chromosomes. It has two complete sets of each pair of chromosomes. During the process of mitosis, these sets of chromosomes are equally distributed to each of the new cells.
 
When a mutation occurs in the genes that regulate the cell cycle or the mitosis process, errors can occur. You can end up with one cell getting 0 or 1 copy of a chromosome while the other can get 3 or 4 copies.
 
This leads to what is called gene dosing problems. If you have 4 copies of a growth driver gene in a single cell, it can lead to increased signals for growth.
 
Translocations happen when a chromosome swaps a section of itself with another chromosome. There is a high level of these translocations in blood cancers. One of the most famous translocations is the Philadelphia Chromosome.
 
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This is the name given to the Chromosome 9/22 translocation. It's often called the BCR/ABL translocation and plays a major role in CML. This translocation occurs when part of chromosome 9 gets switched with a section of chromosome 22.
 
This kind of translocation is called a reciprocal translocation. The presence of a translocation can be a good prognosis for one kind of cancer and a poor prognosis in another.
 
Translocations come in many kinds to include and insertion or deletion of part of a chromosome into another. A section of chromosome can be inverted.
 
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In cancer, you will see many genetic mutations that result in deletions or duplications of a specific gene. One such case of a deletion is EGFR exon 19. It is often associated with a favorable prognosis in lung cancer.
 
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In this type of deletion, only part of the actual gene is lost. In this case it's the 19th exon. A case of a duplication is the MET amplification.
 
This is where the MET gene gets copied multiple times. This occurs in about 20% of NSCLC with an EGFR mutation. These can have greater than 12 copies of the MET gene.
 
Single base substitutions are one of the most common mutations. This is where one amino acid is coded in place of the original one. In the world of proteins, the structure of the protein determines function.
 
A change of a single amino acid can completely change the way the protein behaves. These substitution mutations can cause a kinase to be in the always on confirmation or render another protein completely inert.
 
Proteins are long strands of amino acids so a substitution mutation uses a specific format. The first letter represents the original amino acid that is supposed to be in that position. Then it is followed by the position in the protein.
 
Finally, it's followed by the letter for the amino acid that is actually in the mutated protein. So if you see a KRAS G12C mutation, that means the original Glycine at position 12 is replaced with a Cysteine.
 
If you see a KRAS G12V mutation, that would mean the same Glycine at position 12 is replaced with a Valine.
 
Base substitution mutations cause there types of effects with Silent mutations, Nonsense mutations, Missense mutations and Frameshift mutations.
 
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The silent mutation has an error in the base, but it still encodes the same actual amino acid. This causes a mutation, but has no effect hence the name silent mutation. Some amino acids even have the same attributes so a substitution has no effect on the overall protein.
 
The Nonsense mutation is when a base is changed and causes the codon to encode a premature stop signal. This gives you a non functional truncated version of the protein.
 
 
The Missense mutation is the most common. The base substitution alters the amino acid and alters the overall function of the protein. This is the case in Sickle Cell Disease.
 
A single base mutation drives a pathologic disease. It can also lead to a growth kinase being stuck in the on position.
 
The frameshift mutation is the worst. It occurs when 1 base is added or deleted. This shift every single codon in the entire gene. The whole protein is thrown off. This would be like taking a paragraph and shifting all the spaces so none of the words make sense. 
 
 
Proto Oncogenes and Tumor Suppressor genes 
 
 
A Proto-oncogene is one of those genes that drives cell growth through the cell cycle which can mutate and become an oncogene that drives cancer growth.
 
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These are the many genes that make up the growth receptors and signal transduction pathways inside a cell. There are a lot of these growth factor receptors on the surface of cells.
 
They fall into families like Epidermal Growth Factor, Vascular Endothelial Growth Factor, Platelet Derived Growth Factor, Fibroblast Growth Factor, and many more.
 
When mutations occur in these receptors, they can stay in the on state even when there are no growth signals around to activate them. This drives the cell into the cell cycle and promotes cell proliferation.
 
The next set of proto-oncogenes occupy the transduction pathways that translate the activation of the growth receptor into the nucleus.
 
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These genes are the cascades of proteins and enzymes inside the cell that translate receptor activation into gene activation inside the nucleus. These are broken down into specific pathways that control specific functions of the cell.
 
They fall into the Mitogen Activated Protein Kinase (MAPK) pathway and the mTOR pathway. There are others like the Wnt and Hedgehog pathways.
 
These pathways are made up of many proteins that can mutate like RAS, RAF, MEK, ERK, PI3K, AKT, and so many more. When these proteins mutate the growth of the cell can be locked into an always on state.
 
The last major pathway of gene that can mutate into oncogenes to drive cancer are in the control the the cell cycle through mitosis.
 
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This is governed by the Cyclins and the Cyclin Dependent Kinases. There are many other proteins and enzymes in these checkpoints. Mutations in any of them can allow the cell to advance through the cycle without proper growth signals.
 
The tumor suppressor genes are those that block the cell from growing when it's not required. Many of the growth pathways are regulated by factors that prevent them from being activated without the proper growth signals.
 
One such example is RAS gets turned back off by NF1 which is a tumor suppressor gene. In the mTOR pathway the PIP3 gets turned back to PIP2 by PTEN. These are some of the many tumor suppressor genes in the growth pathways.
 
The most famous of tumor suppressor genes is the p53 gene. It is known as the guardian of the genome. It is responsible for ensuring the integrity of the DNA before allowing a cell to copy its genome.
 
p53 is activated by all of the DDR pathways to arrest the cell cycle for DNA damage repair. There are other internal checkpoints the cell must clear during the growth cycle to ensure everything is good before allowing it to move to the next stage of growth.
 
The loss of a key tumor suppressor gene is called a loss of function mutation. If you have 1 good copy of a tumor suppressor gene, it will still function. It takes a loss of both alleles of these genes to lose function.
 
Many times in cancer a the tumor suppressor genes like p53 are lost, but not by mutation. They become silenced by epigenetic forces such as methylation from carcinogens.
 
 
 
Epigenetics in Oncology 
 
 
The term epigenetics means on top of genetics. This is the study of how DNA is packaged, regulated and expressed. The basic unit of DNA packaging is the nucleosome.
 
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This includes all the histones and DNA that makes up one nucleosome. It's about 104 base pairs of DNA wrapped around eight histone proteins.
 
There are two H2a, two H2b, two H3 and two H4 histone proteins made into an octamer. The tails on the histone proteins can be modified with different chemical groups like Acetyl groups, methyl groups, phosphates, and ubiquitination.
 
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The patterns of modifications on these histone tails can increase or decrease the expression of that gene. If you add a methyl group to the promoter of the gene on the DNA, it can silence the gene.
 
If you add it to the right place on the histone tail, it will increase expression of that gene. The addition and removal of acetyl groups on the histone tails will modify the charge on the histones and its ability to bind the negatively charged DNA.
 
These additions or removal of acetyl groups is done by enzymes and will allow or deny access to that section of DNA for gene transcription. This is done by Histone Deacetylases (HDAC) and Histone Acetyltransferase (HAT) enzymes.
 
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The way the DNA is packaged plays a big role in how genes are expressed. It doesn't take a mutation in a tumor suppressor gene to cause it to be lost. The process of DNA methylation can silence genes.
 
The way the DNA is packaged plays a big role in how genes are expressed. It doesn't take a mutation in a tumor suppressor gene to cause it to be lost. The process of DNA methylation can silence genes.
 
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This blocks the binding of the RNA polymerase and prevents expression of that gene. This can happen from environmental effects.
 
There are enzymes called DNA methyltransferase (DNMT) that add these methyl groups. There are 2 versions. The first will add new methyl groups to the DNA adding to current methylation patterns on the DNA.
 
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The second only replicates current DNA methylation patterns as the DNA gets copied. So why in the world do cells need to methylate DNA anyway? This is how genes get silenced as we develop that are no longer needed.
 
Epigenetics is all about understanding how our environment can alter the way our DNA expresses certain genes. It's about how the choices we make can alter the way our DNA expresses certain genes.
 
The study of genetics is all about the physical structure of the DNA, but epigenetics is about how the environment can alter the way DNA is expressed.
 
 
Targeted Therapies
 
 
Current Chemotherapies take a very broad approach to trying to stop cancer. They tend to have limited efficacy and carry a lot of side effects. They attempt to block cancer by inhibiting cell replication and growth.
 
Most of them interfere with the process of mitosis by blocking the process like drugs that inhibit the centrosomes and spindles. Other chemotherapy agents will damage DNA to a point of cell death. Some do this by cross linking the DNA strands.
 
These approaches are very broad and have side effects on healthy cells. They cause a lot of toxicity related to hair loss, GI problems and blood count drops. They inhibit all rapidly replicating cells good and bad.
 
One of the most rapidly developing cells in the body are all the blood cells like red blood cells, platelets and white blood cells. This leads to anemia, clotting issues and tons of infections.
 
Targeted therapies have grown in use over the past few years. For all they do, they still only apply to about 20% of cancer patients. They are very powerful drugs for those patients who do benefit from them.
 
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Many of these drugs are a simple pill or a few pills each day. They are really easy to use for both doctors and patients. They do have side effects based on their gene of target, but not nearly as much as chemotherapy.
 
Targeted therapies target specific mutations in cellular pathways that driver cancer growth. The first generation targeted therapies targeted very broad targets like EFGR. They inhibited the EFGR activity, but they inhibited it in all cells with that receptor.
 
Newer generations of targeted therapies target specific mutations of these pathways that only exist in the cancer cells like EFGR L858R mutation or KRAS G12C mutations. These have very powerful benefits for patients with one of these mutation drivers.
 
Since there are so many pathways in the cells from the growth receptors, the growth pathways, the cell cycle checkpoints and the DNA damage repair pathways, we have a just scratching the surface of these targeted therapies.
 
One of the biggest downsides to targeted therapies is how specific it really is. The cancer cells often mutate and get around it after a while. Then they have to develop a new inhibitor for that newer mutation.
 
Synthetic Lethality falls into the targeted therapies space. Cancer cells, when they mutate often become highly dependent on the remaining working pathways.
 
The concept of Synthetic Lethality says that taking out 1 gene leaves the cancer cell working just fine. We have to find 2 genes that, when targeted together, become lethal.
 
An examples is Gene A gets inhibited, but the cancer cell goes on as it increases use of Gene B. If we combine an inhibitor of Gene A with an inhibitor of Gene B, we can kill that cancer cell.
 
IntraTumor Heterogeneity 
 
 
The tumor begins with just one mutation, but as it continues to replicate cells, it will begin to develop newer and newer mutations. Each generation will have new mutations the original cells did not have.
 
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In most tumors the amount of cells with a specific antigen to be targeted is only a small population of the entire tumor. One tumor might express NY-ESO in 75% of the cells and the next might only express NY-ESO in 10% of the tumor cells.
 
This accounts for some of the wide variability in responses for patients with a therapy to a specific antigen.
 
In some indications like blood cancers, there are only a few mutations or antigens available to target. You will see many companies targeting antigens like CD19 or BCMA. This is because these cancers are made up of B cells which express a few antigens to be targeted.
 
Therapies targeting these antigens do really well as there is little variability in the antigens of Blood cancers. In solid tumors, the amount of possible mutations or antigens that can be targeted can be in the dozens or even hundreds.
 
The amount of mutations or antigens across a tumor is known as its heterogeneity. This can make it very difficult to target these tumors and any one antigen might only be present in a few tumor cells.
 
 
Antigen Shedding 
 
 
You can get a therapy that reduces the tumor for a while, but then it relapses. The is due to the concept of antigen shedding.
 
This is a concept that comes from targeting specific antigens or mutations in a tumor. The tumor may have a lot of different antigens and mutations. If you treat with a particular target like CD19, you will kill all the cells with CD19, but might not kill all of the tumor.
 
That means all those remaining cells that do not express CD19 can regrow the tumor and the patient relapses. This makes the patient unable to respond to that same treatment again.
 
That is when a new target has to be found to kill the remaining clones like the B and C clones in the picture above. This is why so many solid tumors are difficult to kill. They have at least some cells that resist the current treatment and lead to tumor regrowth.
 
 
InterTumor Heterogeneity 
 
 
The final concept is intertumor heterogeneity. This concept says that many patients with the same tumor might all have different mutations driving their cancers.
 
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This is easily explained with Non Small Cell Lung Cancer (NSCLC). You can take a dozen patients with NSCLC, and every one of them can have a different mutation. One might have an EFGR driver mutation, another might have RET, ROS1, ALK or any number of other mutations.
 
Every patient has very unique tumor antigens. Some are shared called public antigens. Public antigens tend to be antigens common to that cell type or common mutations in that cancer.
 
Others are completely unique to that single patient called neoantigens. Neoantigens are mutated versions of normal healthy proteins. These unique mutations can become antigens to target.
 
This greatly complicates treatment of cancer. Every patient in unique and every tumor is unique. 
 
 
 
 
 
 
 
 
 


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