ATM Gene Mutation and the Risk of Cancer
Ataxia telangiectasia (ATM) is a rare inherited disorder that affects the immune system and the nervous system, among others. It is a protein that is part of a specific protein kinase family, namely phosphatidylinositol-3 kinase enzymes. Put simply, these enzymes are like an army of soldiers that are involved in several regulatory processes within the cell. These include cell cycle regulation, becoming active when DNA is damaged, interloc us recombination (a genetic process that is beyond the scope of this article) and telomere (telomeres are regions at the end of chromosomes that protect them from degrading) length control. The role of ATM is like the sergeant that regulates the DNA double-strand break (DSB) repair pathway as well as all the other aforementioned processes.
It is clear to see that any faults in the functioning of ATM can lead to disease. Specifically, any factor that is involved in cell repair, as well as chromosome protection, is obviously a major player in disease development. The ATM gene codes for the ATM protein, which is why mutations that disrupt the gene’s proper function prevent it from encoding the protein properly. This, in turn, affects the protein’s function to regulate the cell’s cycle, to becoming active upon DNA damage as well as during interlocus recombination telomere length.
Based on this alone, it is clear to see how mutations—or DNA sequence errors—in ATM can be behind these diseases. Mutations in the ATM gene have been linked to cancer so much so that they are used as genetic markers for the disease. What this means is that individuals who carry the mutation are much more likely to develop cancer at some point in their lives than those whose genome does not carry it. In fact, it has been shown that certain mutations in ATM are associated with a 40% to 60% risk of breast cancer at an advanced age. More specifically, individuals who inherit the mutation from either parent are at relative risk of breast and ovarian cancer (approximately up to 52% to 69% lifetime risk depending on the mutation) as well as other types of cancer, including pancreatic cancer, prostate cancer, lung cancer, as well as several other types.
With such a high risk of hereditary breast cancer, it is not surprising that national guidelines suggest that women who carry—or even potentially carry—the aforementioned ATM mutations screen themselves to reduce the risk for breast cancer starting at the age of 40. Furthermore, risk prevention, as well as management options, include things such as a breast exam, mammogram, and breast magnetic resonance imaging (MRI). There is also the option to consider mastectomy (a medical term referring to the removal of one or both -) as a means of risk prevention and management. This is especially important for women who have a personal or family history of cancer, for whom the breast cancer risk is even higher.
Let’s dive into the science of it just a little bit deeper. Everyone has two copies of the ATM gene, one inherited from their father and one from their mother. If either of the parents carries the ATM mutation, it is likely that it will be passed on to their children, and this immediately makes them carriers of that mutation. Furthermore, let’s first mention that the primary cause behind many forms of cancer is DNA damage and the associated lack of mechanisms to fix that damaged DNA.
The reason why this mutation is so problematic is that ATM is one of four genes that are particularly important for DNA repair during cell division. We won’t burden you with all of them, but ATM, as well as breast cancer 1 (BRCA1), are two of them. ATM and BRCA1 are needed to repair the breaks that occurred in the DNA strand. Otherwise, these unattended breaks will eventually lead to a cancer-associated lack of destruction of faulty cells and their subsequent accumulations that lead to tumors.
Furthermore, at the beginning of the article, we mentioned ATM, the protein, as being crucial for the maintenance of cell health by virtue of phosphorylation (a process that adds a molecule to proteins and thereby regulates their function). Namely, ATM phosphorylates a protein that is particularly important for regulating programmed cell death that is a normal physiological response of removing cells that have too much DNA damage to be replicated. This protein is called p53. However, it is also referred to as tumor protein p53, cellular tumor antigen, phosphoprotein p53, and tumor suppressor p53, to name a few. Interestingly, the protein is also referred to as “the guardian of the genome” as it functions to protect the genome and maintain its stability. By virtue of being phosphorylated by ATM, p53 subsequently causes several other genes to become active (we’ll spare you the pathway), which culminates in the aforementioned cell death (also called apoptosis) and the protection of genes/DNA from damage.
So, to tie it all back to mutations of the ATM gene and the potential risk of cancer, it should be a bit clearer now how any kinds of irregularities within that gene cause diseases. Furthermore, it should definitely be clear now how these mutations specifically cause cancer.
Ultimately, however, it should be highlighted that studying genetic markers inherently investigates the likelihood of an individual suffering from a condition. This means that there is a chance that a person whose ATM gene has specific mutations has a significantly increased risk of developing cancer during their lifetime, though this is not 100% certain. This simply means that, relative to individuals without the mutation, those who do have it are at a higher risk and ought to conduct further testing as well as monitoring to maintain informed. If the prediction turns out to be positive, knowing early on that there was a risk for it increases one’s chances for management as well as a possible cure. In other words, there is a certain level of uneasiness about knowing what future your genes point to, but there is also comfort in knowing one is prepared to tackle it.