MUTATIONS AND CANCER DEVELOPMENT
Cells are continuously exposed to DNA damaging events but due to the efficiency of the repair machinery only a small proportion of these are retained, that is, become somatically acquired mutations. For the development of most cancers, the estimate is that between five and fifteen ‘driver’ mutations, that is, mutations in critical genes, are required. From whole genome sequencing, we now know that these are typically part of a spectrum of tens of thousands of mutations in tumour cell genomes. The two main classes of ‘cancer genes’ are oncogenes and tumour suppressors. In the former gain-of-function and are dominant; in classical tumour suppressors, gene function is lost. In addition, micro RNAs can also play important roles in cancer development through their capacity to regulate the expression of both oncogenes and tumour suppressor genes.
The list of things that can give us cancer has grown so long you might be inclined to wonder how it is that we don’t all get cancer at a very early age. In fact, most cancers develop very slowly, in part because we have evolved ways of repairing our DNA when it has been damaged so that only a small proportion of the lesions actually become ‘fixed’ in the genome. As we’ve seen, causes of DNA damage include high-energy electromagnetic radiation (γ rays, X-rays and UV radiation) and atomic particles emitted by radioactive atoms (α and β particles). This ionising radiation can damage DNA in two ways: (1) directly (e.g. by causing breaks that lead to chromosomal translocations and deletions); or (2) indirectly by interacting with water (radiolysis) to generate reactive oxygen species (ROS). The ROS formed are the hydroxyl radical, hydrogen peroxide and the superoxide radical.
The hydroxyl (free) radical is one of the most reactive of all chemicals because it readily removes an electron from any molecule it encounters, converting that molecule in turn into a radical (usually called a free radical, a highly unstable, reactive molecule with an unpaired electron). This is a problem, given that we can’t avoid external mutagens (radiation and chemical carcinogens). But it’s worse than that because we make these very reactive free radicals as by-products of some normal cellular reactions.
We’ve also seen that some of our food contains cancer-causing chemicals (e.g. polycyclic aromatic hydrocarbons, aromatic amines, alkylating agents). Electrophilic carcinogens react with nucleophilic sites in the purine and pyrimidine rings of DNA, forming covalent links (‘adducts’). These chemically modified bases in DNA can result in errors in repair and hence mutations. The main reason why smoking is such a powerful contributor to the cancer statistics discussed earlier is several potent carcinogens that form a wide range of DNA adducts.
We have three lines of defence. The first lies in what we eat. The reason why we are so often told to eat fresh fruit and vegetables is that they contain several antioxidants that scavenge ROS (e.g. vitamin C and α-tocopherol) and so confer a degree of protection. The second is that we have evolved a number of cellular enzymes (e.g. superoxide dismutases) against free radicals. These provide a biochemical buffer by reacting with the dangerous by-products of normal metabolism and converting them into harmless substances.
Nevertheless, despite these protections, it is estimated that the genome in a normal adult human cell acquires ~20,000 DNA lesions (i.e. chemically damaging hits) per day. Many of these might result in mutations if the modified, damaged DNA was not repaired correctly. Thus, the third and most important protective mechanism is a variety of DNA repair processes that correct nearly all of the lesions formed. Of the 20,000 distinct DNA ‘hits’ per day, on average less than one of these remains in the DNA to be passed on when the genome is replicated. Mutations, therefore, accumulate at the rate of one every day or two to give ~10,000 mutations over a lifetime.