## Cancer begins at the genetic level

Cancer has accompanied mankind since time immemorial, so it is not surprising that attempts have been made to explain its occurrence. For some cancers, it has been possible in the past to identify a definite cause - a certain aspect of the environment. For example, skin cancer was found to be caused when people were frequently exposed to UV-laden sunlight. Ernest Hemingway, in his 1952 book The old man and the Sea, wrote about skin spots caused by frequent sun exposure or while fishing. Environmental factors that cause or promote tumour growth are called carcinogens. To date, more than 1,000 substances are known to be carcinogens to some degree, and this number is constantly increasing. Carcinogens can be of various natures: biological (viruses - e.g., papillomavirus, responsible for cervical cancer), chemical (smoking, chemicals - e.g., asbestos), or physical (UV radiation, radiation).

Environmental factors may contribute to the development or progression of the disease, but the main cause of tumour transformation is always genetic alterations or changes in gene expression caused by changes in the epigenome (see chapter 7 for more details). These changes can occur even without the influence of the external environment, because of the natural error rate of DNA polymerases that copy DNA before cell division. Essentially, these are "errors" in information, with errors in some genes being much more dangerous for cancer development than others. Mutations in 3 groups of genes are particularly dangerous (Figure 9.3). The first group is the proto-oncogenes, which code for proteins that activate division in healthy cells and prevent premature cell death. The standard proto-oncogene of a healthy cell can transform into an oncogene that promotes cell division and blocks cell death, even if this is not appropriate for the cell. Another group are the tumour suppressors, which ensure that cells do not divide too early. Tumour suppressors also support the cell when it realizes it is damaged, so that the cell dies according to plan and harmlessly, not affecting the surrounding cells. However, when the tumour suppressor gene is damaged, the resulting protein blocks division and promotes the death of the damaged cell. Combined with the ease of division caused by the activated oncogene, this leads to uncontrollable cell division. A third, very important group of genes are those that code for proteins that are important for maintaining DNA integrity. Their job is to correct DNA mutations, and if this is not done, the mutations accumulate.

But what is the cause of the deletion of a tumour suppressor gene or activation of an oncogene? The mechanism of conversion of a proto-oncogene into an oncogene is often that the gene is shifted within the DNA and thus enters the domain of another promoter that triggers its expression differently (Figure 9.4). Duplication of the gene into multiple copies may also occur and simultaneous point mutations in which only one nucleotide is changed are not uncommon. A nucleotide substitution in a gene may result in an amino acid exchange. However, a point mutation can also have an effect in a non-coding region that serves to regulate gene expression. If the result is that too much oncogenic protein is produced, the protein is more active, or the resulting protein is resistant to removal, it is enough for a point mutation to occur in just one copy of the gene (in one allele), and the cell has a problem. The effects of such a change are dominant and occur even if the second allele of the gene is perfectly fine.

The mechanism of damage to tumour suppressor genes and DNA repair genes differs in part from the activation of oncogenes. These genes are more likely to have point mutations or complete gene deletions, or a change in their epigenetic regulation, e.g., methylation of the promoter, which prevents transcription of the gene information and formation of the protein. The main difference is that mutations in tumour suppressor genes and repair enzymes result in the loss of function of the protein derived from one allele of the gene, but the product of the second (functional) allele is usually sufficient to ensure function. A mutation in both alleles of a gene is therefore necessary for the development of cancer, since the effect of the mutation in this case is recessive. However, it must be said that the body has several safeguard mechanisms in place, so a mutation in only one gene is not sufficient. For the development of cancer, a combination of several mutations in genes are required, with the order in which the changes occur is also important.