Chordoma Foundation

Genetic Risk Factor Discovery Q&A

What exactly was discovered?

  • More than 95% of individuals with chordoma have a single-letter variation, called a SNP, in the DNA sequence of a gene called brachyury. Specifically, the SNP is a change in the DNA sequence from G-C to a A-T. Approximately 75% of patients have the variation in both copies of the brachyury gene, while the remainder have the variation in one copy of the gene.
  • Having this SNP is associated with a five-fold increase in the risk of developing chordoma.
  • Having two copies of the altered brachyury gene is associated with higher levels of brachyury expression in chordoma tumors

What is a SNP?

A SNP  – short for single nucleotide polymorphism – is a single letter change in an individual’s DNA sequence. Any two unrelated people have about 99.5% of their DNA sequence in common, but at certain sites in the genome some people might have an A, while others have a G. Such a site is called a SNP, and each of the possible spellings at that site is called an allele.

Most SNPs have no effect at all, but some SNPs influence traits such as eye color, or can cause predispositions to diseases like cancer or Alzheimer’s disease.

Why is this discovery significant?

  • It confirms that the gene brachyury contributes significantly to the development of chordoma in nearly all chordoma patients, not just familial chordoma.
  • It provides further evidence that brachyury could be a therapeutic target for chordoma, and could aid in the development of an effective treatment.

What does this discovery mean for chordoma patients?

This study tells us that most chordoma patients have a particular variation in the brachyury gene. It is not known whether having this SNP, whether one copy or two, affects the prognosis for chordoma patients.

In the short term, this discovery will not impact the treatment of chordoma. However, in the future, it could lead to a better understanding of how chordoma develops, and how to most effectively treat it.

Are family members of chordoma patients at risk?

Blood relatives of chordoma patients who have the chordoma-associated brachyury SNP are also more likely to have the SNP than the general population. However, even if a person has the SNP, the risk of developing chordoma is still extremely low – less than 2 in a million.

How does this discovery effect the development of new treatments?

This discovery may help enable the development of a drug that works by targeting the brachyury pathway.

Researchers have already shown that shutting off the production of brachyury in chordoma cells causes them to stop growing. By studying how the chordoma-associated SNP changes the brachyury protein, it may be possible to identify ways to reverse the alteration or block its affect. Specifically, scientists may be able to identify a drug that inhibits the function of brachyury or other genes regulated by brachyury.

Does this mean that the cause of chordoma has been discovered?

Not exactly, but it does aid in our understanding of how chordoma develops. Given that the variant of brachyury associated with chordoma is relatively common in the general population, and chordoma is extremely rare, there must be other factors involved in developing chordoma. Otherwise, many more people with that variant would get chordoma. This discovery strongly indicates that the brachyury gene plays an important role in the development of chordoma, but it is likely not the only player. More research is needed to determine what actually triggers the development of chordoma.

Is it now possible to predict who will get chordoma?

It is now possible to determine who is more or less likely to get chordoma. However, even for those more likely to get chordoma than the general population, the risk is still very, very small. Individuals without the chordoma-associated SNP have virtually no chance of getting chordoma, while individuals with the chordoma-associated SNP have a 2 in a million chance of getting chordoma.

How can I find out if I have this SNP?

Several companies offer personal genome-wide analysis services that could detect this SNP (See: personal genomics providers).  Check that the companies cover the rs2305089 brachyury SNP in their analysis. For example, the personal genomics company 23andMe offers a mail-order kit for genome-wide SNP testing, which will detect the chordoma-associated SNP.  If you have already had your genome analyzed by 23andMe you can determine your brachyury SNP status here. 23andMe reports either a C or a T at the rs2305089 marker; the T variant is the one that is associated with chordoma.

Should my family or I get tested?

Right now, knowing that you have the chordoma-associated version of brachyury will not make any difference in your or your family’s health. It is a matter of personal preference whether or not you want to know.

If you would like help in deciding whether to get tested you may want to consider contacting a genetic counselor through the National Society of Genetic Counselors.

What should I do if I have the SNP?

If you have already been diagnosed with chordoma, having the SNP will not change the treatment options available to you. You should continue seeking care from a physician experienced at treating chordoma.

If you have the SNP but do not have chordoma, you are in good company; nearly 40% of the global population has the chordoma-associated SNP. However the overwhelming majority of people who have this SNP will never get chordoma. Even if you have the SNP, your chance of getting chordoma is still less than 2 in a million.

At this point, there is nothing known to reduce the risk of developing chordoma. If you are concerned about your risk of getting chordoma, talk to your doctor.

What does this discovery mean for chordoma research?

Finding a SNP in the brachyury gene that is so strongly associated with chordoma raises important questions and creates a number of potential opportunities to further advance the understanding and treatment of chordoma. Several lines of research will flow from this discovery, including:

The SNP loads the gun, but what pulls the trigger?
It appears that a SNP in brachyury can create conditions that promote the development of a chordoma, but alone it is not sufficient to cause the disease; some other cooperating factor is needed to actually set the process in motion. The next phase of the Chordoma Genome Project aims to determine the genetic event(s) that trigger the development of chordoma both in people with and without the SNP.

How does the SNP promote the development of chordoma?
The SNP in the brachyury gene causes the protein encoded by that gene to be produced differently. But it remains to be determined how that change impacts the structure of the protein and its function. Scientists will want to determine how the altered brachyury protein interacts with other genes and proteins in the cell to cause cancer.

Once a chordoma has formed, is the altered form of brachyury critical to the survival of chordoma cells?
The brachyury SNP appears to play a role in the initial development of chordoma, but it is not known whether it continues to be important once the disease has process has been set in motion. Answering this question will help determine the value of brachyury as a target for treatment.

Is there a way to reverse the effects of the SNP, and does doing so stop the growth of chordoma cells?
We already know that inhibiting brachyury in-vitro (in a petri dish) causes chordoma cells to stop growing, but there is currently no way to inhibit brachyury in humans. Once we determine how the SNP does its damage, that could potentially enable the development of drugs that reverse effect of the SNP, either by inhibiting brachyury directly or blocking some downstream consequence of the SNP.

Answering these questions could prove critical to developing effective treatments for chordoma. But this research will only be possible if researchers have the funding they need. Please consider donating to the Chordoma Foundation so that we can drive forward the research needed to answer these important questions.

Is this finding relevant to other diseases?

There is mounting evidence that brachyury plays a role in several different types of cancer, including lung cancer, colon cancer, and pancreatic cancer. This finding provides additional evidence that brachyury is an important cancer gene, and future research spawned by this discovery may shed light on how brachyury contributes to the development of other cancers. Ultimately, that knowledge could lead to the development of new treatments that are useful for multiple types of cancer in which brachyury plays a role.

Interestingly, the SNP found to be associated with chordoma is also associated with increased improvement in lung function in response to inhaled corticosteroids in patients with asthma.

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