Dr. Xavier Llor

The evolution has been extraordinary and just so, over the past 10, 15 years. So, we started from the inexpensive test where we were guessing what the gene could be, what the defective gene could be, according to what the patient and the families were showing. And then if that test was negative, we were considering of going to a different test to check for another gene who could be-that could be responsible for that process. So that was expensive and often time consuming because we were not finding mutations in the initial trial. So, this has evolved to you having more genes that are responsible for diseases as we will learn from and those genes packaged within tests are now encompass a number of genes that are being tested at the same time. What we call multi-gene-panel test. These are now the ones that are-we are commonly using. They allow us to really test for differing genes that can be responsible for similar cancer susceptibility and therefore they really let us to be much more efficient in terms of diagnostics. So, that has really revolutionized how we do genetic testing. And it has allowed us to really be much more efficient when it comes to genetic testing. So, changes are happening, they are happening fast, and the capacity of these panels to incorporate new genetic defects that we are learning every day, that are responsible for cancer susceptibility are easily incorporated. And that also led us re-check patients who are tested several years ago and some of those genes who were not discovered by that time yet, so we can go back to those individuals who tested negative at that time and double-check, see if those new mutations that have been discovered are actually the ones that are causing their cancer predisposition

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And so again I think that whatever that information two years ago, it’s already different nowadays, and probably in two years it’s still going to be different. Therefore, it’s an active field that we really need to make sure that our patients do understand that our knowledge keeps evolving and we need to really keep in touch with our patients so they can actually benefit from the new knowledge.
 

So, in general Lynch syndrome is a multi-- what we call multi-cancer syndrome. So, while colon and endometrial cancer are the ones that carry the highest risk for Lynch syndrome, in fact it’s a multi-cancer syndrome where there are other organs that have also carry a high risk of cancer: from ovaries, to the rest of the GI tract, to the urinary tract. So, it has to be approached as such, as a multi-cancer syndrome. The Lynch syndrome is due to mutations in a set of genes that are called mismatch-repair genes. And their job is really fixing particular types of defects in the DNA daughter chains that are created. Those defects do happen on a regular basis as daughter chains keep getting created, our body’s not that perfect, but our body has those mechanisms to really fix those defects. When those genes are mutated, they cannot do their job of fixing those errors, and those errors start propagating in the new cells that are generated, becoming cells that are not well controlled and that’s how cancer evolves in Lynch syndrome. In general, cancers do develop fast in Lynch syndrome, even though the prognosis in general is better, but the key thing for Lynch syndrome is very early diagnosis so that we can catch cancers early. In general the cancer risk varies for colon, for instance, in Lynch syndrome, you can go from 12% for one of the mutations call PMS-2 to about 50% for the more common-- or the genes that carry a higher risk. So, there’s quite a bit of variability. So, it’s important for us to know which is the particular gene that is causing Lynch syndrome. And the other types of cancers we talk about also vary depending on the type of gene. For instance, the endometrial cancers have a high association with MSX-6, another mismatch repair gene. So, those are important details so Lynch syndrome as a whole is an entity, but it has a lot of flavors and often they depend on the particular gene that is affected. And, when it comes to Lynch syndrome we’ve identified individual who carry the genetic defects. We do have surveillance strategies, chemo preventive strategies, and also surgical interventions that can prevent cancer. For colon, colonoscopy is a well-accepted procedure that does help prevent colon cancer. It has to be done very-- every one to two years to make sure that we catch the cancers early enough because as we said those cancers evolve fast. For endometrial and ovarian cancer risk often it comes down to discussing hysterectomy after childbearing age most of the time. So, they are interventions that are really tailored to the patients. Aspirin as a chemo preventive agent has been found to be a very effective agent when taken in high doses. So, there are studies going on right now trying to identify lower doses that have a significant preventive effect for cancer too. So, there are things on the horizon and the chemo preventive world too. So, in general, we have learned a lot about Lynch syndrome, we’re still learning a lot, but we do know how to effectively prevent cancer in Lynch syndrome, and that is why it’s so important to diagnose it. And that’s why it’s important to diagnose it in individuals who never had cancer before so we can actually prevent the development of cancers.

 

How has it changed for you as a clinician to give people a Lynch diagnosis?
Right, so it really has evolved tremendously from 10 years ago, or so, where having a Lynch syndrome diagnosis and the particular gene that was causing it made little difference to us and we all thought that they all had a very high risk of cancer and therefore they really had to be counselled in a very similar way, to now that we’ve learned so much more about the specific risks by gene that actually we’re starting to propose to no longer talk about Lynch syndrome in general but saying emolage 1 Lynch syndrome, emissige 2 Lynch syndrome, emissige 6 Lynch syndrome, because what it means having one mutation versus another is very different. And that’s what we’re trying to tell our patients and that’s why little by little we’re tailoring more surveillance and recommendations to their own specific mutations. That is really more of a personalized approach, and as we learn more, we’re really developing surveillance recommendations more tailored to those specific genes. And we’ll hear more. As we learn more about modifiers and other things probably be able to narrow the choices for every single person even more. So again, what we were saying several years ago, based on the knowledge at that time, has changed quite a bit now, and I’m very sure in a few years it’s going to be very different from what we are seeing today. So, I think that emphasizes the importance of keeping in touch with cancer genetics programs for patients, because what we told one may change. It’s extremely likely that it’s going to change in the future, and so they can benefit from more updated information.