This article is for anyone who is interested in learning about their potential genetic cancer predisposition that might have contributed to the onset of an existing or prior condition, or for those who have not developed cancer yet, but are worried they might be predisposed due to family history.

The type of DNA testing discussed in this article does not cover identifying potential treatments for cancer. Such DNA testing is also an important option for those who have been diagnosed with cancer and will be discussed in another post.

For your genetic cancer predisposition DNA testing, it boils down to two choices: you will have an option between a gene panel versus the full genome. A gene panel examines a certain number of genes in your DNA which were preselected for a previously well-established association with cancer predisposition - which can range from two genes to multiples of dozens. The full genome in turn examines all of your inherited DNA (in scientific speak, it is also referred to as germline DNA).

Gene panels for cancer predisposition

Pros:

• Cheaper than a full genome sequencing, with gene panels ranging from as low as few hundred dollars to approximately $2000-$3000 CAD. The reason for the high cost: clinical accuracy. The cheaper the DNA test you go with, the higher the likelihood of false positives/negatives (but especially false negatives). We covered this topic of DNA testing cost previously

• Gene panel DNA tests have been used clinically for a decade now, first launched by Ambry Genetics in 2010. As a consequence, use and clinical interpretation of gene panel DNA tests comes with incredible experience, with millions of patients being tested all around the world. As such, some companies are incredibly experienced in the medical interpretation of DNA data derived from gene panels, and can arguably boast of offering the best clinical tests for cancer predisposition in the world

Cons:

• Only tiny fraction of the actual genome is analyzed. If your cancer predisposition stems from mutations in regions of DNA that are not being analyzed by gene panels, you will not find out. Once again, it comes down to DNA tests providing false negative information which we explained in this post related to prenatal testing

Full genome sequencing for cancer predisposition

Pros:

• You obtain your full genome which means you are not just analyzed for cancer predisposition, but all currently known genetic conditions that can be detected based on current knowledge. Therefore you obtain:
  i) cancer predisposition
  ii) other genetic conditions, either diagnosis or predisposition
  iii) carrier status (doesn't affect you but can impact future generations)
  iv) pharmacogenetics - information on how you react to medications based on your genetics
• Full genome DNA testing, depending how the procedure is performed, can reveal a significant amount of information on what is referred to as DNA structural mutations. These are the type of DNA mutations that affect large segments of DNA in one go - such as large deletions, duplication of DNA content, insertions of new information from a different region of the genome, DNA code flipping around, or even a funky mysterious combination of all these. Typically such large scale events in your genome require additional technology to be uncovered, and gene panels are usually quite limited in this scope (a high quality clinical test will employ these additional technologies to get to the bottom of this information, driving up the cost of the test, if you were wondering why some cancer predisposition tests are so cheap compared to others – the devil is always in the details)
• Full genome also allows for re-analysis for any potential health problems in the future. As opposed to a cancer specific gene panel which will really limit the future re-analysis to cancer only and only to the genes that have been selected for testing in the first place. With full genome, there is no limit to what the DNA data is studied for in the future
• The value of that DNA data extends beyond an individual's life for multiple generations of that individual's progeny. In other words, your DNA data will be of potential value to your kids, and their kids, and their kids' kids, especially if it is a complete data like your full genome. This is still a fairly abstract notion for people to consider, but we have covered the topic of legal protection of your genome data to secure future benefits of its use for your family. It is well worth the read

Cons:

• Greater expense than gene panels. Currently Merogenomics provides access to a medical full genome sequencing DNA test for as low as $4,099 CAD - this price is if the testing would take place using one of our participating clinics offering the test along with medical oversight. It is about $3,700 if your selected doctor would be ordering the test. Your doctor does not have to work at one of the participating clinics for you to get the test, but Merogenomics can easily set up interested clinics with medical DNA testing
• The overall patient numbers who have had their full genome sequenced is vastly smaller than those who have had gene panels delivered – it is still numbering only in hundreds of thousands of people (that is to be expected for full medical genome analysis as gene panels are more preferred option in medical setting due to cost. Toronto Sick Kids is already calling for adopting full genome across the board for all genetic testing in Canada, so you can appreciate where the trend is heading). As a consequence, the field of accurate clinical interpretation of full genomes is not as vast when compared to clinical use of just gene panels, but it is still growing.

If you are only interested in cancer predisposition then a gene panel from one of the best leading companies in the world might be a smart way to go, as long as you understand the limitations: we are only looking at pre-selected genes. If your genetic predisposition to a cancer development is outside of the investigated segments of DNA, you will obtain false negative results. But with the right company, you can get one of the best hereditary cancer predisposition DNA tests on the planet in terms of quality and experience of medical interpretation.

If you want more information for you and your kids (and their kids or other closely related family members) to be able to take advantage of that information, go with full genome sequencing. Apart from the clinical report, the most valuable aspect of the process are is actually the benefits of having your own DNA data particularly for a couple of purposes:
i) re-analysis in the future if additional health problems arise,
ii) passing it onto progeny for their benefit (if they encounter health problems, having parental DNA data for comparison can be very valuable).

Thus you need to decide, do you prefer a smaller investment for an already well established clinical process to obtain on-the-spot predisposition identification (if any exist) but with potentially no future utility of your data, or do you want a more expensive option that captures all information, the ownership of which can be passed on to future family members (meaning you would have to do this legally) so they can utilize that information in the future as needed (even if you are fully negative now in your results).

Augmenting your cancer predisposition knowledge

Besides the type of DNA test that can be considered in terms of scope of analysis, there are additional options that can be considered to enhance the amount of information that can be obtained from your DNA test. These options are already available on the market, hence we mention it here. They are still fairly novel options but they can have profound benefit for the patient, and are worth mentioning in detail. Depending on the DNA test provider, these additions can be included at no extra cost.

The first enhancement we will mention is use of RNA sequencing. First, a bit of a background. Everyone knows that DNA is the book of life, an encrypted code made up of four chemicals that informs the cell on how and when to produce its large molecular structures. But DNA does not provide that information directly. Rather, it uses intermediary snippets of information in the form of RNA. Think of DNA as more like a filing cabinet of information. RNA is a copy of a small section of DNA (called a gene) and it is the RNA that is actually used as a blueprint for cells to build your molecules that do all the work inside your body. There are other types of RNA as well but they will not be relevant to this educational piece.

Therefore, testing for RNA accomplishes two things:

• It confirms that the mutation observed in DNA is real because it is also observed in RNA
• More importantly, it can capture mutation events that are either not observed in DNA or would not be obvious that the DNA mutation is pathogenic. When RNA is produced, it is made up of tiny fragments of information copied from DNA and spliced together to produce mature RNA that is the final blueprint. Sometimes you can have mutations in the DNA that will affect this splicing together which can produce an aberrant blueprint, and as a consequence, an aberrant molecule. If that molecule plays an important role, and that role is removed, like controlling cell division, it can result in cancer. We would never know this except when we see that RNA splicing is affected in certain patients when we test their RNA

Therefore, adding complimentary RNA analysis for hereditary cancer predisposition can even further increase the diagnostic yield of the DNA test. This is still a very unique extra service (when it is offered) that further increases the quality of the DNA test results.

The second interesting test enhancement is what is referred to as the polygenic risk score.

But before we explain this concept, let’s dive into an explanation of what is investigated in cancer predisposition DNA tests. Typically, a set of genes known to be involved in cancer development are assessed to see if there are any DNA mutations in these genes that might affect their proper function. Such mutations are typically of a large impact scale where a single mutation can either knock out a gene or over-activate it. This can be contrasted to other types of DNA mutations that only have a small effect, sometimes almost imperceptible effect, such as a small decrease in the activation of the gene. Understanding of these small-scale mutations is much more difficult to decipher because their biological impact is not readily obvious. But we do know they exist and in many cases, which mutations they are.

In recent years, there has been increasing interest in understanding what these type of small impact mutations might do together collectively. Thus, what is referred to here as polygenic means collecting DNA mutation information from many different areas of the genome together and understanding how these mutations might be influencing the probability of someone getting cancer. These DNA mutations can be present outside genes that are typically assessed for cancer predisposition, even in areas of the genome that do not code for genes. Thus polygenic risk score is a probability that is calculated that someone is at increased or decreased chance of developing cancer if they have certain amount of these DNA mutations that individually are of small biological impact, but together can have dramatic influence that may drive cancer development. We covered this concept in detail previously when describing complex genetic conditions which materialize due impact of many genetic mutations.

Polygenic risk scores are notoriously difficult to create especially with high enough accuracy for clinical use. While many universities are involved in development of such polygenic risk scores in their research, these are still exceedingly rarely available commercially. We have previously discussed a polygenic risk score for Type II diabetes that was also for educational purposes and not for clinical use. Very few providers offer actual clinical polygenic risk score for cancer development (typically breast or prostate cancers).

Such polygenic risk scores normally only apply for individuals who themselves have not yet had a personal cancer episode and so can inform these people with greater accuracy on their lifetime risk of developing cancer. These can be very powerful in helping doctors manage patients, so it is unfortunate how rarely available polygenic risk scores are used by doctors. But we are still in an uphill battle for more broad use of DNA testing in cancer predisposition or other medical areas so let’s be patient. But if you are looking for a cancer predisposition test, and you have not yet been diagnosed with cancer, additional polygenic risk score on top of the typical cancer predisposition genes that would be assessed might be super valuable to you and your doctor, so it very well might be worth your while to bring it up with your doctor.

It is worth stressing that these are serious tests and should definitely be discussed with close relatives, especially for the full genome test, as you will be potentially finding out additional information besides the cancer predisposition. With the full genome, you will literally look into 50% of your own siblings, parents or kids’ genetic code. So, at that point, are you willing to discover additional information about yourself (that could have health management implications) and would your close relatives be willing to learn that as well? This question is important to ask your family for cancer predisposition, but with full genome sequencing, there are hundreds of potential medical outcomes, some of which are debilitating untreatable conditions with onset in late life. While you might tolerate discovery of such information, others might not.

To learn more about the types of tests discussed in this article, you can compare details of all cancer medical DNA tests offered through Merogenomics site.

This article has been produced by Merogenomics Inc. and edited by Jason Chouinard, B.Sc. Reproduction and reuse of any portion of this content requires Merogenomics Inc. permission and source acknowledgment. It is your responsibility to obtain additional permissions from the third party owners that might be cited by Merogenomics Inc. Merogenomics Inc. disclaims any responsibility for any use you make of content owned by third parties without their permission.

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