This transcript has been edited for clarity.
Hello. I’m Dr. David Johnson, professor of medicine and chief of gastroenterology at Eastern Virginia Medical University. Welcome to another common concern of his G.I.
Today I wanted to provide some perspective on genetic testing. colorectal cancer: What’s required, what’s standard, and what you need to know now.
Genetic testing for colorectal cancer has only become available in recent decades. This is what he said in 1991. APC Genes that tend to cause Familial adenomatous polyposis. Only two years later, an abnormality in the mismatch repair gene was recognized. MLH1, MSH2and PMS2 — These identified what was then called hereditary polyposis colon cancer and is now known as Lynch syndrome. Since then, the field has truly evolved and many other genetic tests have been created.
Here we come to the present, and the question arises: what must we do now and why?
Number of patients with possible Lynch syndrome in your practice
It is estimated that approximately 1 million people in the United States have Lynch syndrome, but the majority do not know it. Lynch syndrome is an autosomal dominant disease. Lynch carrier frequency is estimated to be approximately 1 in 280 patients and currently accounts for an estimated 3% to 4% of cancer cases in the United States.
A little math here will help gastroenterologists determine how often we see this in our practice. First, we need to recognize that there may be a referral bias that makes it even more common. Since you are a gastroenterologist, patients may be sent to you because they have polyps or a family history.
With this in mind, let’s say the estimated frequency is about 1 in 200 people. Assuming that in the clinic he has 12 patients for half a day and 4 sessions, her number of patients will be 48. Two full days a week, he performs 15 endoscopies on 30 patients. So if you do the math, you’ll see 1 to 2 hereditary colon cancer patients every month, or 12 to 24 Lynch syndrome patients a year. And if you have her 10 GI providers, which is what I do, that’s going to develop into about 100 to 240 patients a year.
So I would like to ask you, where do you find such patients in your clinic?
Standard tests for Lynch syndrome
Regarding the measurement and definition of Lynch syndrome, we are particularly focused on the mismatch repair frequency defect, which occurs in 15% to 20% of sporadic cancers.
If clinical testing is performed, microsatellite instability (MSI) assessment or immunohistochemistry (IHC) testing is required. They also require pathology-level expertise, which is certainly less demanding than sequencing the genetic abnormalities currently identified in germline testing for Lynch syndrome. It’s not a thing.
These two tests are not the same. IHC measures mismatch repair proteins expressed in a sample, and MSI measures mismatch repair function by detecting changes in DNA that occur when critical mismatch repair function is lost.
The performance of both MSI and IHC tests is very good. As for the sensitivity of the test, it is around 95% to 100%. It’s a little less specific.
The main advantage of IHC compared to genotyping by MCI approaches is that they do not require an on-site molecular laboratory, as they are available in the routine service of general pathology laboratories.
There are several caveats regarding IHC staining. IHC tests are most reliable with fresh or frozen tissue samples, but tend to be much less reliable when using tissues preserved in wax or other chemicals. So instead of going back and digging tests out of your pathology archives, you need to do them on the front end.
Another caveat is to be aware of the expression of mismatch repair proteins after treatment, although this is very rare. If a patient is currently receiving chemotherapy or checkpoint inhibitors, neoadjuvant therapy may actually reduce protein expression. This can lead to false positives in IHC tests.
If we look at this and say the MSI or IHC is “normal,” what does that mean? Does it completely rule out Lynch syndrome? A normal value may exist, but this is rare. Alternatively, we could consistently produce microsatellites skilled at mismatch repair. This is more common in the presence of: PMS2 And that MHS6 These genes are on the very rare end of the Lynch syndrome spectrum.
So when we talk about Lynch syndrome, we’re not talking about MSI or IHC testing, we’re talking about germline susceptibility. This means ordering these germline tests.
premiumFive predictive model
One of the predictive models you should know about is the latest one. premiumFive. This is a predictive model for discrepancy repair. This is important because if you limit your testing to oncology testing, it will only be relevant to cancer patients. If you are trying to prevent cancer by testing probands, you are missing an opportunity.
premiumFive The model was developed by people at Dana-Farber Cancer Institute and Harvard University, who have now expanded the predictive model to include genes targeted by Lynch syndrome. MLH1, MSH2, MSH6, PMS2and EPCAMwhich is an epigenetic silencer. MSH2.
This model has proven to be very good at discrimination. For all five genes, the identification rate is approximately 83%.If you just have it PMS2 For mutations, the discriminant is much lower, around 60%. But again, when you do germline testing for Lynch syndrome, you rarely see this mutation.
There are several considerations to be aware of when initiating these genetic tests, including some notable challenges. In particular, when germline testing is initiated in patients with colon cancer, pathogenic gene testing abnormalities can range from 10% to 16%. These are especially more common in Lynch syndrome.Especially it can be seen Mutiwhich is a genetic DNA excision repair gene and is associated with a higher risk of colon cancer.
Some of these genetic profiles undergo up to 82 genetic tests. So you start to see some noise around it, especially around what are called variants of uncertain significance. Unfortunately, this is not uncommon.
in one study Researchers evaluating patients undergoing genetic colon cancer testing in Ohio found that about 47% had some form of this difference of uncertain significance. This would certainly cause a lot of problems because if we started expanding germline testing or mandating genetic counseling and follow-up for these patients, it would overwhelm the current system. .
new data about Muti gene
Another interesting finding that I would like to highlight to you is that Muti, alter excision repair genes. This gene is increasingly recognized to be part of a biallelic profile. These are autosomal recessive genes, as opposed to the autosomal dominant genes found in Lynch syndrome.
a recent research They studied about 60,000 European patients with colorectal cancer from three different major colorectal consortia and compared them with about 71,000 patients of European descent. They observed no increased risk. Muti If you only have a monoallelic pathogenic variant. No risk association with colon cancer was established.
When we start looking at the frequency of this single allele in the normal population, Muti, we can see that it is basically approaching the population frequency. As a result, current recommendations are evolving into the idea that it is unwarranted to alert these people to the need for further colon cancer surveillance or other surveillance.
Latest guidelines from the National Comprehensive Care Network (NCCN)
NCCN Guidelines updated They recommend that all colon cancer patients under the age of 50 undergo germline testing. These are serum tests and multigene panel tests for colon cancer associated with Lynch syndrome and other related colon cancers.
Reflex testing should be performed on all of these patients, regardless of age. All pathology labs should test her MSI and IHC.
If positive, we go back and do germline testing on these people, regardless of their age.
If the test does not return a positive result, clinical judgment is required. This means taking the family history of these patients. If you see anything that suggests symptomatic cancer, it’s a good idea to start a conversation with those people. If there is no evidence of family history, NCCN recommends that people should be offered these gene panels, not as a mandatory responsibility, but as an option they would like to offer during the discussion.
Support for germline testing is further reflected in: Latest Delphi initiatives It is a treatment for early-onset colon cancer and has developed international management consensus guidelines. They agree with the NCCN guidelines that germline testing is warranted for all patients under 50 years of age.
summary
I have a few take-home messages that I would like to leave you with.
Make sure your pathology lab performs MSI and IHC.
Perform reflex testing for all colon cancers under age 50.
All patients should be offered germline testing, which is now the standard of care. For patients who are IHC or MSI positive but have not undergone germline testing, this option should be discussed. However, IHC- or MSI-positive individuals, regardless of age, should undergo germline testing and serological testing.
I’m going to throw a lot of alphabet soup at you, but I hope it gives you some perspective as we begin to talk about this very important topic related to colon cancer. We can and certainly need to do better.
I’m Dr. David Johnson. Thank you for listening.
Regular Medscape contributor David A. Johnson, MD, is a professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia, and a past president of the American College of Gastroenterology. His main focus is clinical gastroenterology. He has published extensively in the internal medicine/gastroenterology literature, with a primary focus on the effects of sleep and the microbiome on diseases of the esophagus and colon, and more recently on gastrointestinal health and disease..
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