Mutations and Cancer
Art & Research: Melanie Collana
Further Reading Literature: Alyssa Sorensen
Mutations
A mutation is an error in DNA sequence that occurs during replication of cells, exposure to radiation or chemicals, etc..
Most mutations are fixed through a proofreading step where the enzyme DNA polymerase checks for any incorrectly placed nucleotides (DNA bases) and corrects them during DNA synthesis.
If there are a series of incorrect nucleotides in a sequence, then they will be taken out through a process called excision where that section is cut out.
Types of mutations
Some mutations are not harmful. Silent mutations do not affect the reading of the DNA sequence. For example, if a codon (three DNA bases in a row) reads GUG and is mutated to read GUC, it will still code for the amino acid (a building block of proteins) valine in both cases because there is redundancy with coding for amino acids (Science Direct).
However, while many mutations can be repaired, some mutations will not be corrected as the repair machinery in cells is not 100% efficient. If this mutation is not a silent mutation, it will cause a change in the reading of the sequence. Such mutations include insertion and deletion.
Insertion and deletion
Insertion is when an extra nucleotide is added and a deletion is when one is missing.
Insertion and deletion mutations are some the most dangerous mutations because they cause a frameshift. This means that everything after the mutations will be read incorrectly, since the nucleotides in codons are read in threes.
Mutations to tumor suppressor genes can be especially dangerous.
When a cell goes through mitosis (or cellular division), the DNA replicates along with other organelles. This is one event where mutations can occur.
Cell cycle
There are important checkpoints throughout the cell cycle that keep cells from dividing indefinitely and collecting DNA sequence errors.
Although there are many checkpoints, there are three major ones. The G1 checkpoint is especially important because if it is passed, the cell will most likely go through mitosis.
The G1 checkpoint checks for cell size, sufficient growth factors, and DNA damage (Khan Academy). Growth factors are important as they help with cell proliferation. Any cell that fails at a checkpoint will go to the G0 phase, where cells do not divide, or will undergo apoptosis (Khan Academy).
The G2 checkpoint checks for DNA damage and complete DNA replication (Khan Academy).
The M checkpoint checks that the chromosomes are completely attached to spindle fibers so that they can be evenly distributed between the daughter cells after division (Khan Academy).
Protooncogenes
Before we touch back to mutations we should cover two important aspects that contribute to cancer. There are two gene types called proto-oncogenes and tumor suppressor genes.
Proto-oncogenes are responsible for encoding products that promote cell division, and inhibit cell differentiation and cell death. Such products include growth factors and their receptors, cell cycle regulators, proteins, transcriptions factors, and more (Nature).
Tumor suppressor genes
Tumor suppressor genes are responsible for preventing cells from dividing uncontrollably. These genes work to repair DNA damage, and tells the cells when they need to self-destruct (Nature).
Like any other gene, both proto-oncogenes and tumor suppressor genes can be mutated. The mutated form of a proto-oncogene is called an oncogene.
Transition into oncogenes
There are multiple ways that a proto-oncogene can become an oncogene, one way which is by a mutation.
If there is a mutation in a proto-oncogene, it can cause over-activation (where the RNA and proteins encoded by this gene are produced at a higher rate) in which case the proto-oncogene is now an oncogene (Nature). Depending on the organ system, there are situations in which only one allele needs to be mutated for cancer to arise from an oncogene (NCBI - "Tumor Suppressor Gene").
Oncogenes encode oncoproteins that allow cells to grow without the need of growth factors and accelerate the cell proliferation process that can cause a tumor to form (Science Direct).
This would be characterized as a gain-of-function mutation because the proteins are now more active than prior to the mutation(s) (NCBI - "Tumor Suppressor Gene").
Mutation in tumor suppressor genes
Faulty tumor suppressor genes can also be dangerous. While oncogenes work to accelerate abnormal cell growth, inactivated tumor suppressor genes will not stop cells from growing out of control.
This is characterized as loss of function mutation (NCBI - "Tumor Suppressor Gene"). This can also lead to a tumor and eventually cancer (NCBI - "Tumor Suppressor Gene").
Unlike oncogenes, a tumor suppressor gene requires mutations on both alleles to change the phenotype (Science Direct). This is known as the two hit Hypothesis (Science Direct).
It is important to know that it does not just take one mutation of either protooncogenes or tumor suppressor genes to cause cancer, but rather the accumulation of these mutations over time.