The Genetics Of Risk: Breast Cancer

In the ongoing series “The Genetics Of Risk” we examine the genes that underlie increased cancer risk in a variety of different types of cancer. One of the most famous sets of genes that when mutated are associated with an increased risk of cancer are BRCA1 and BRCA2, which are specifically linked to a highly increased risk of breast and ovarian cancer.

The BRCA1 and BRCA2 genes encodes instructions for making a molecule that is involved in repairing DNA when it breaks. DNA is kept under very close wraps in the central nucleus of the cell, and it contains the essential blueprint for the functioning and behavior of the cell. When this blueprint is tampered with, cells are at an increased risk of tail-spinning and giving rise to a tumor. One of the ways mutations form is by the cell making mistakes when repairing a routine break. DNA breaks for all sorts of reasons – including toxins such as nicotine or harmful UV radiation. When one or both strands of DNA break (which is known as a single or a double stranded break), a large group of proteins assembles around the gap in order to repair it. Since the two strands of DNA are complementary to each other (that is, the information on one side matches the information on the other side like a lock with its key or an old-school photograph with its negative) when only one strand of DNA is broken, the molecular machine tasked to repair it can use the other strand as template to repair it. However, when both strands are broken, the situation is more complex. Fortunately, the human genome is composed of two copies of each gene. This means that the cell can use the other copy of the gene to work out what is supposed to be in the gap. This process is known as homologous recombination. BRCA1 and BRCA2 are two key components of this mechanism.

When BRCA1 and/or BRCA2 are mutated and cannot function properly the breaks in DNA cannot be repaired properly. This means that the cell is much, much, MUCH more likely to “make a mistake” when repairing a break. This increased chance of making a mistake is known as “genomic instability” – which means that these mistakes (that are really mutations) are bound to accumulate and snowball. The more mutations there are, the more likely it is that more mutations will come up. Cells protect themselves from mutations by having a complex system of checks-and-balances, molecular machines that are primed to scout out mutations and either repair them or press the “self-destruct” button on the whole cell. As mutations break down the different checks-and-balances within the cell, more and more new mutations are likely to go undetected. This in turn makes it more and more likely that the cell will cross the line and start replicating uncontrollably, eventually forming a tumor.



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