BRCA genes are more complicated than most people think

BRCA genes are more complicated than most people think

Genes long considered risk factors are about much more than cancer: they help DNA repair

Rachel Aronoff

Molecular Microbiology

Trying to find out what might cause cancer, or possibly increase the risk of developing cancer, has been a big driver of medical research since the first "war on cancer" was declared in 1971. Now, the realization that genes which determine cancer risk can possibly help us prevent it is gaining ground. Some of the first genes identified as risk factors for cancer, the BRCAs (BReast CAncer genes) are really about much more than breast cancer.

Genetic analyses of DNA from families in which repeated generations of women under 40 succumb to breast or ovarian cancer allowed the identification of two BRCA genes. The first one was mapped to chromosome 17 in 1990. As one of the "winners" of an international race to find the BRCA1 gene, ultimately cloned in 1994, the biotech company Myriad Genetics obtained exclusive patents on methods to test for mutations in the genes. This monopoly on BRCA testing contributed not only to expensive testing fees, but also to the inability of patients to ask for second opinions, which persisted until a landmark decision by the Supreme Court in the case Association for Molecular Pathology v. Myriad Genetics in 2013: genes could no longer be patented.

While this decision overturned at least some of Myriad's BRCA patent claims, the long monopoly on testing created a general knowledge gap about just how the mutated genes acted differently than their functional counterparts. While the patent protection was allowed, the exact genetic changes that made the BRCAs a familial risk factor for breast cancer could be kept secret. Not even the patients' doctors knew the basis for their molecular diagnostics.

'Cancer-causing' vs inactivity

The normal function of these genes, on the other hand, has been shown through work in many laboratories: these genes act together to enable repair of complete breaks across the two strands of the DNA double helix (double-stranded, or ds, breaks), in particular allowing perfect repair of damaged DNA by so-called "homologous recombination" in cells. We carry two copies of each chromosome in our cells, and homologous recombination uses the undamaged copy as a template for exact repair of the damaged one. (At least two other types of less effective DNA repair pathways exist in our cells.) The BRCA genes also have particular functions in DNA replication and large-scale movements of DNA within the nuclei of cells, also know as chromatin remodeling.

In fact, the "cancer-causing" BRCA genes in families prone to breast cancer are not making any special toxic molecules that result in breast cancer: they are simply not working, so cells are unable to repair DNA damage correctly.

Our cells are subject to damage from all sorts of sources. Radiation, like that from x-rays or plane travel, causes double-strand breaks in DNA. Additionally, internal cellular processes from metabolism to DNA replication can result in formation of DNA breaks that need to be repaired.

In the absence of active BRCAs, repair of DNA damage becomes much more error-prone - in particular, due to one of the alternative means of ds-break repair known as "non-homologous end joining," which can be thought of as a sort of panic response to DNA damage in cells but is also crucial for immune system function. The new mutations that result from this type of repair increase the overall risk of cancer development.

To put this more concretely: if a woman inherits a mutated BRCA gene from her family, the absence of the BRCA function means repair of DNA damage will occur by error-prone molecular pathways, allowing a gradual acquisition of new mutations in other genes, which can result in cells growing out of control, accumulating further errors and ultimately progressing into full-blown cancer.

With and without DNA repair

Carriers of the BRCA mutation, it is important to note, still have one functional copy of the gene that can repair DNA damage by normal homologous recombination in cells. Between 35 and 55 percent of "carriers" do not develop breast cancer in the course of their lifetime, so drastic clinical recommendations without talking about DNA repair strike me as very questionable.Without an inherited mutation in these genes, about 12 percent of women get breast cancer. These statistics come from cancer.gov, a website that, tellingly, discusses "harmful" BRCA mutations, rather than clarifying that it is simply their inactivation which is relevant for cancer progression.

What has been rarely acknowledged, although this is gradually becoming more widely known, is that the loss of correct DNA repair activity due to mutation in these BRCA genes increases the risk of developing many other cancers, including leukemias and lymphomas, melanoma, pancreatic or colorectal cancers, and even prostate and testicular cancers. These genes are really about much more than just breast cancer, and they particularly highlight the importance of preventing DNA damage. 

When BRCA carriers are only told that they have an increased breast cancer risk, these patients aren't getting the whole story. It might be helpful, for instance, if they were given information about ways to avoid the cell damage that their mutated BRCA genes are unable to repair correctly. To encourage earlier or more frequent mammograms, for instance, for someone carrying a mutated copy of the gene makes little sense, remembering that some of this patient's cells might already have lost the second functional copy of the gene, and that x-rays induce double-stranded breaks in DNA.

A recent paper reviews the current status of genetic diagnostics and medical interventions based on these BRCA genes. As authors Amanda Toland and Paul Andreassen, who study human genetics and cancer biology in Ohio, wrote:

"Notably, competition in the market-place has helped make testing more affordable. Collectively, these events have led to increased rates of individuals being tested for mutations in BRCA1 and BRCA2, and an increased need for interpreting the significance of variants that are identified." 

Crucially, they recommend that the many different BRCA variants observed in patients should be assessed in terms of their actual ability to repair DNA.

DNA is subject to many forms of damage, some of which are entirely natural and some of which can be due to environmental pollutants. When cells can repair their DNA, these normal processes are not a great problem. But when BRCA genes don't function, the inexact repair can become dangerous.

Preventing DNA damage

If the absence of accurate DNA repair promotes cancer development in general, could reducing damage to DNA help prevent it? I certainly believe so. While in no way wanting to do any victim blaming, there are simple ways to reduce personal and secondary levels of DNA damage that I recommend.

Avoid cigarette smoking: not only do combustion products in smoke directly damage DNA, some chemicals in cigarettes also inhibit repair processes. Additionally, suntanning, drinking alcohol, solvent exposure (for instance, when painting or doing projects around the house), pesticide use, hair coloring, straightening, or perming are all common activities that can increase damage that BRCA genes normally would make sure could be repaired correctly.

Ideally, the manufacturers of products known to induce ds-breaks (or even DNA damage in general) would find alternatives that are less risky for cells. Understanding that these strong risk factors are due to an inability to correctly repair DNA could, in the meantime, provide a reason for people to try avoiding such products and habits. Some degree of cancer prevention through changes in common habits is possible.

Any questions?

Ask Rachel Aronoff