Gene mutations are core to the development and progression of cancer. Only a few genes have been directly linked to the development of hereditary cancers yet those that have have been shown to drastically increase the chance of developing the disease. Perhaps the most notable hereditary gene to date is the BRCA gene (breast cancer susceptibility protein) which has been strongly linked with an increased chance of developing a range of cancers, most notably breast and ovarian.

Referring to BRCA as a single gene is not specifically correct as there are two major forms that influence cancer development: BRCA1 and BRCA2. BRCA1 and BRCA2 are both key components in DNA repair mechanisms that prevent DNA damage passing onto further generations of cells. Because of their protective roles against the passing on of incorrect or mutated DNA, BRCA1 and BRCA2 are referred to as tumour suppressor genes.

DNA Damage and Repair

DNA damage tends to represent itself in the form of a single-strand break – where one of the two sugar-phosphate backbones of a DNA strand is broken – or a double-strand break – where a DNA strand has been broken clean into two pieces. BRCA1 and 2 are responsible for the repair of double strand breaks through a process known as homologous recombination (HR).

Homologous recombination is one of two repair mechanisms a cell will utilise in the event of a double strand break; the second mechanism is called non-homologous end joining (NHEJ). NHEJ is a much more primitive version of DNA repair that involves two segments of DNA being rejoined without the use of a template. Because of this, NHEJ is a much more error prone repair mechanism as it can introduce mutations relatively easily into a cells DNA.

Take, for example, a DNA strand that has experienced two double-strand breaks simultaneously, one four nucleotides further along the strand than the original break. The result would be three DNA sequences: two lengths of DNA with a four base sequence cut out of the middle. If the two lengths of DNA are rejoined using NHEJ then the four nucleotide sequence would be lost and the resultant ‘repaired’ DNA is no longer correct. DNA deletions like these result in mutated proteins which further result in abnormal cell behaviour.

As we each inherit two of the same chromosome – one from our father and one from our mother – we have two copies of any particular gene. In HR, the non-damaged version of a gene can be used as a template to reproduce the original DNA sequence. This is where BRCA1 and 2 come into play. Each protein is a major contributor to the repair process involved in HR, mainly by activating machinery proteins such as Rad51. With their loss, the mechanism can not work and the cell is left with the much more error prone mechanism NHEJ. All of a sudden the importance of BRCA1 and 2 becomes very clear.

Treating BRCA Mutations

A new drug has been found to show ‘excellent anti-tumour activity’ in a total of 70 patients across a range of different cancers including breast and ovarian. The drug itself has yet to be given a trade name (currently referred to as BMN 673) and is a member of a promising class of drugs called PARP inhibitors.

PARP is a protein that is immediately activated following a single-strand break in DNA. Once activated, PARP attaches to the site of a single-strand break and begins to create a long chain of amino acids which acts as a signal to repair machinery. Inhibiting PARP means that a cell is unable to designate and repair single strand breaks which, in a normal cell situation, would not be a problem as the cell would still be able to utilise other repair mechanisms such as HR. However, in a cell that for some reason can not utilise HR, a single strand break is a HUGE problem. When a single-strand break occurs opposite another single-strand break, a double-strand break is formed – this is a very strong signal for a cell to undergo programmed cell death. And what cell would not be able to repair a double-strand break through HR? A cancer cell with a dysfunctional BRCA1 or BRCA2 gene.

Synthetic Lethality

This method of treating cancer is one of the most intriguing theories to date and is referred to as synthetic lethality – synthetically inducing a combination of mutations in order to kill a cell, when a single mutation does not. 

Synthetic lethality is a revolutionary way of approaching cancer treatment and theoretically could be carried over to mutations in other genes in order to treat other cancers that do not have a BRCA mutation.

The PARP inhibitor itself has been shown to have a significantly positive effect in 11 out of 25 ovarian cancer patients and 7 out of 18 breast cancer patients with little to no side effects. Although this may not seem much, considering there are no current targeted therapies for patients with BRCA mutations, this is a huge development. Women with a harmful BRCA1 mutation have about a 5 times higher risk of developing breast cancer than women without the mutation (60% instead of 12%). They also have a 15-40% risk of developing ovarian cancer at some point in their lives compared to 1.4% in women without a harmful mutation.

Future Impact on Cancer

With celebrities including Sharon Osbourne and Angelina Jolie each having opted for a double mastectomy (removing both breasts) to prevent the development of breast cancer at some point in their lives, the public have suddenly become aware of just how much of an effect a BRCA mutation diagnosis can have. Currently women have to consider drastic operations much like their celebrity counter-parts which can result in not only a physical impact but a huge psychological impact also. Furthermore, BRCA mutations have been found in other malignancies such as prostate cancer.

A treatment such as this has the potential to become universal for any patient with a BRCA mutation, no matter what form of cancer they have or their gender. Therefore news of a targeted therapy against the mutation is one to be recognised, not only for the ingenious thinking behind it but also for the revolutionary effect it will have on future generations of cancer patients.

References:

The original press release by the Institute of Cancer Research: http://www.icr.ac.uk/press/press_archive/press_releases_2013/23753.shtml

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