Genetics
There is not a cancer gene, but instead there are variant alleles of certain genes that can influence the chances of a cancer forming. These variant alleles can be obtained either by inheritance from a parent’s genes, or exposure to mutagenic environments like radiation or chemicals. There are two main categories that will be discussed; proto-oncogenes and tumor suppressor genes.
Proto-oncogenes
Meaning ‘earliest mass’, proto-oncogenes are the earliest form of a gene that has the potential to mutate into an allele whose protein product has the potential in cancer formation. In the event that one of these proto-oncogenes develops a genetic mutation, it would turn into an oncogene, or an allele whose protein product results in an abnormal increased rate of mitosis, which then could lead to a cancerous tumor. Oncogenes can be thought of as throttles, because their protein products act as an accelerator pedal, which speeds up cell division.
A type of proto-oncogene is HER2. HER stands for human epidermal growth factor receptor. The protein that the HER2 gene encodes for plays an important role in the growth of epidermal tissue. The HER2 gene is about 4000 nucleotides long, and codes for a protein that consists of 1255 amino acids.
At nucleotide 1963, the wild-type HER2 Gene should have an adenine base, which in turn would result in the codon ATC being translated into the amino acid Isoleucine. However, if the base is a guanine instead of an adenine, then the codon GTC translates to the amino acid Valine. One study showed that cisgender women with the valine version of this gene had anywhere from a 20% to a 160% increased risk of developing breast cancer, due to just this one single nucleotide.
But why does this single nucleotide change result in that much higher risk of developing cancer? The HER2 Gene codes for the HER2 Protein, which is a transmembrane protein. When it is activated by another protein called the epidermal growth factor receptor, it sets off a series of chain reactions that result in DNA replication, followed by mitosis. So a change in the HER2 protein’s shape due to this mutation may lead to an increase in its efficiency, leading for it to call for cell division more frequently than it should.
Other studies have found that in around 30% of breast cancers, there’s an overabundance of the HER2 protein. If there’s an overabundance of the HER2 protein, it means that the HER2 gene was overexpressed, or that it gets translated into a protein more often than it should. Gene overexpression can occur when there’s a mutation in the gene’s promoter sequence, leading to more frequent transcription (which leads to more frequent translation). If this was the case of the HER2 gene, then there would be an increase in the amount of the HER2 proteins, which would then increase the rate at which cell division occurs. This increase in cell division has the potential to lead to a cancerous mass forming.
Tumor Suppressor Genes
If proto-oncogenes are the accelerator pedals to the formation of cancerous masses, tumor suppressors are the breaks. The proteins that are produced as a result of the translation of tumor suppressor genes are able to do one of two things when they encounter cells with mutations. If able, they are able to repair the damaged DNA within a mutated cell. Or, if the damage to the DNA is too severe to be able to be repaired, tumor suppressor genes can also trigger apoptosis within the mutated cell. If a mutation occurs in one of these tumor suppressor genes, then it could worsen its ability to catch and repair mutated cells, thus potentially losing a key defense mechanism against cancer forming.
One of the most well-studied tumor suppressor genes is known as TP53. TP53 is located on chromosome 17, and it has more than 20,000 nucleotides. However, once the introns are spliced out, the mature mRNA strand has around 2,600 nucleotides. Once the 5’ and 3’ untranslated regions are accounted for, the gene TP53 codes for the tumor suppressor protein known as P53, which is 393 amino acids in length. When DNA in a cell gets damaged, either due to UV radiation, mutagenic compounds or other carcinogenic agents, then P53 can do one of two things: if the DNA can be repaired, P53 can activate other genes to produce proteins needed for that repair to occur. If the DNA is too far damaged for repairing to be possible, P53 will prevent the cell from dividing, which will ultimately lead the cell to undergoing apoptosis. However, a mutation within the TP53 gene could change the amino acid composition (as well as the function) of the protein P53.
On the coding strand of the DNA, at nucleotide 743, there should be a guanine. However, if this gets changed to an adenine, thus changing the codon from CGG to CAG. This means that the amino acid would change from arginine to glutamine. This seemingly insignificant change decreases the effectiveness of the P53 protein, and could make someone more susceptible to cancer. Similar effects would occur if there was a substitution mutation from a cytosine to a thymine at position 382; a guanine to an adenine at 532; a guanine to an adenine at 818; a guanine to a cytosine at position 841; and a guanine to a thymine at position 844. All of these small changes to this TP53 gene can change the shape of the resulting protein, and a change in the protein’s shape can change how well it works. If the P53 protein isn’t effective enough in repairing DNA or signaling for apoptosis, then a cancerous mass could begin to form.
Elephants are exceedingly resistant to developing cancer. Even though elephants can live up to eighty years old, they still have relatively low rates of cancer occurrence. One of the reasons behind this is because elephants have twenty copies of the TP53 gene on their DNA. This means that if one copy picks up a mutation that makes it less effective over time, then they still have nineteen other copies protecting their cells from cancer. In humans, however, a mutation involving the TP53 gene would be much more detrimental, seeing that humans only have a single copy of the gene.
The BRCA genes are also categorized as tumor suppressor genes. BRCA is derived from the words ‘Breast Cancer’. There are two BRCA genes; BRCA1 and BRCA2. Both BRCA1 and BRCA2 play instrumental roles in repairing damaged DNA amongst the cells in the breasts, as well as other cells in the body. Again, similarly with the TP53 Gene, if there is a mutation that inhibits either BRCA1 or BRCA2’s ability in protecting the body against mutagenic cell growth, then the risk of developing cancer is heightened.
A particular mutation known to occur within the BRCA2 gene is known as 999del5. It is called this because at position 999, 5 nucleotides get deleted. This deletion leads to a missense, frameshift mutation. This has a detrimental effect on the amino acids that are coded after the 999 position. Now, this is a relatively common mutation, but there isn’t any specific reason that this mutation should occur at any higher rate than other mutations. In fact, BRCA2’s 999del5 mutation was paired with a founder effect.
At some point in the past, an individual who had this specific mutation settled in Scandinavia. This person had relatively high reproductive success, and passed this mutation to their offspring. As the offspring reproduced, they continued to pass the mutation along, and it became a permanent mainstay in those people groups. Not everyone from the Scandinavian region has this mutation, but for someone to have this mutation they must have some Scandinavian ancestry. Cisgender women who carry the 999del5 mutation have about a 40% increased risk of developing breast cancer, and it’s safe to assume that anyone carrying this mutation has an elevated risk as well.