Are You Employing Genetic Testing Correctly for CRC?

This transcript has been edited for clarity.

Hello. I'm Dr David Johnson, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School. Welcome back to another GI Common Concerns.

Today, I wanted to provide some perspective around genetic testing in colorectal cancer: what's required, what's standard, and what you need to know now.

Only in the past couple of decades have we had the ability to perform genetic testing for colorectal cancer. This started in 1991 with the discovery of the abnormality that identified the APC gene that predisposes to familial adenomatous polyposis. Just 2 years later, there was the recognition of the mismatch repair gene abnormalities — MLH1, MSH2, and PMS2 — which were the identifiers for what was then called hereditary polyposis colon cancer and is now known as Lynch syndrome. Since that time, the field has truly evolved and produced a number of other genetic tests.

That brings us to the present day and the question of what you need to be doing now and why you need to be doing it.

The Numbers of Likely Patients With Lynch Syndrome in Your Practice

It's estimated that approximately 1 million people in the United States have Lynch syndrome, but the vast majority of are unaware of this. Lynch syndrome is an autosomal dominant–type disease. The Lynch carrier frequency is estimated to be about 1 in 280 patients and accounts for an estimated 3%-4% of the cancers in the United States at the present time.

Doing a little bit of math here will help determine how often gastroenterologists may see this in our practices. First, we should recognize that there may be a referral bias that makes it even higher than that frequency. Because you are a gastroenterologist, patients may be sent to you because of polyps or a positive family history.

With this in mind, let's say the estimated frequency is approximately 1 in 200. Assuming that you've got 12 patients in a clinic for a half day, four sessions, this gives you 48 patients. If you perform 15 endoscopies for full days, 2 days a week, this is 30 patients. The math, therefore, would say that you should be encountering one to two hereditary colon cancer patients per month, or 12-24 with Lynch syndrome per year. And if you're in a practice of 10 GI providers, which is what I'm in, that would evolve into approximately 100-240 patients per year.

So I'll ask you: Where are those patients in your practice?

Standard Testing for Lynch Syndrome

When it comes to measuring and defining Lynch syndrome, we're particularly looking for mismatch repair frequency deficiency, which occurs in 15%-20% of sporadic cancers.

If we're doing laboratory testing, this requires either microsatellite instability (MSI) evaluation or immunohistochemistry (IHC) testing. They, in turn, require pathology-level expertise, which is certainly less demanding than doing the gene sequencing for the genetic abnormalities that we now identify in the germline testing for Lynch syndrome.

These two tests are not the same. The IHC measures the mismatch repair proteins expressed in the sample, and the MSI measures the mismatch repair function by detecting changes in DNA that occur when you have a major mismatch repair function loss.

The performance of both the MSI and the IHC tests is very good. As far as sensitivities for testing, they're about 95%-100%; the specificities are a little bit less than that.

The primary advantage of IHC, compared with genotyping with the MCI approach, is that these are available in routine services in general pathology labs, so it does not require a molecular laboratory on site.

There are a couple of caveats about the IHC staining. The IHC tests are most reliable if it's fresh or frozen tissue samples and tend to be much less reliable if you're using tissue preserved in wax or other chemicals. Therefore, you want to have testing on the front end rather than to go back and dig these out of the pathology archives.

Another caveat, although a very rarely occurring one, is to be aware of the mismatch repair protein expression following therapy. If the patient is now on chemotherapy or a checkpoint inhibitor, the neoadjuvant therapy may actually reduce the protein expression. This can lead to a false positive for IHC testing.

If you look at this and say the MSI or the IHC is "normal," what could that mean? Does it absolutely rule out Lynch syndrome? There clearly can be a false normal based on the testing done in your laboratory, which is rare. Or you can have a mismatch repair proficient microsatellite stable production. This is more common in the presence of PMS2 and the MHS6 genes, which are very much on the rarer side of the Lynch syndrome spectrum.

Therefore, when we talk about Lynch syndrome, it's not about the MSI or IHC testing, it's about the germline susceptibility. This means you order the germline testing for these.

The PREMM₅ Predictive Model

One of the predictive models of which you should be aware is the most current, the PREMM₅. This is a predictive model for mismatch repair. This is important, because if you limit your testing to tumor testing, that's only relevant to the patients with cancer. If you're going to test the proband and prevent cancer, you've lost that opportunity.

The PREMM₅ model was developed by the folks at Dana-Farber Cancer Institute and Harvard, who expanded the prediction model to include the genes that we now qualify for Lynch syndrome: MLH1, MSH2, MSH6, PMS2, and EPCAM, which is an epigenetic silencer of MSH2.

This model has proven very good for discrimination. For all five genes, the discrimination is approximately 83%. If you just have the PMS2 mutation, the discriminant is much lower, about 60%. But again, this mutation is very rarely seen if you do germline testing for Lynch syndrome.

There are a couple of considerations that you need to be aware of as you start to do these genetic tests, including some notable challenges. In particular, pathogenic gene test abnormalities can be in the 10%-16% range if you start doing germline testing in patients with colon cancer. These are specifically more common for Lynch syndrome. We see it in particular for MUTYH, which is a genetic DNA excision repair gene that has been associated with high risk for colon cancer.

Some of these genetic profiles will go up to 82 gene tests. So you're going to start to see some noise around that, particularly around what we call variants of uncertain significance. This is something that you will see, unfortunately, not uncommonly.

In one study evaluating patients undergoing genetic colon cancer testing in Ohio, investigators found that approximately 47% had some form of this variance of uncertain significance. This will certainly raise a lot of issues if you start to then do expanded germline testing on these patients or oblige them to genetic counseling and follow-up because we'd overwhelm the current system.

New Data on the MUTYH Gene

Another interesting finding that I want to highlight for you is new information on genetic testing for a monoallelic pathogenic variant called MUTYH, which changes the excision repair gene. It's increasingly recognized that this gene is in the biallelic gene profile. These are autosomal recessive genes as opposed to the autosomal dominant genes that you see with Lynch syndrome.

A recent study looked at nearly 60,000 patients with colorectal cancer in Europe obtained from three different major colorectal consortia, who were compared to approximately 71,000 patients of European ancestry. They observed no incremental risk for MUTYH if they just had the monoallelic pathogenic variant. The demonstrated risk association for colon cancer was not there.

If you start to look at the frequency in the normal population of this monoallelic MUTYH, you will see that it basically approaches a population frequency. As a result, the current recommendation is evolving into the idea that it's not warranted to alarm these people that they need to have further colon cancer surveillance or other monitoring.

Latest Guidelines From the National Comprehensive Care Network (NCCN)

The NCCN guidelines were updated in Fall 2023. They recommend that all patients who have colon cancer under the age 50 years get germline testing. These are serum tests and multigene panel testing for colon cancer associated with Lynch syndrome and other associated cancers of the colon.

You should be reflex testing all these patients irrespective of their age. All your pathology labs should be testing for MSI and IHC.

If it's positive, regardless of the age, you go back and perform germline testing on these people.

If they don't test positive, then you need to use clinical judgment. This means taking a family history of these patients. If you find anything suggestive of syndromic cancers, certainly it's recommended for you to strike up a conversation with those people. If there's no evidence of a family history, the NCCN recommends that they should be offered these genetic panels, not as an obligate responsibility but as an option you'll want to extend to them in your discussions.

Support for germline testing is further echoed by the most recent Delphi initiative for early-onset colon cancer, which produced an international management consensus guideline. They concur with the NCCN guideline that germline testing is warranted for all patients under age 50 years.

Summary

There are a few take-home messages I'd like to leave you with.

Make sure your pathology lab is doing MSI and IHC.

Perform reflex testing on all colon cancers in those under the age of 50.

All patients should be offered germline testing, which is now a standard of care. For patients who are IHC- or MSI-positive and who haven't undergone germline testing, you'll want to discuss this option with them. However, anybody who is IHC- or MSI-positive, irrespective of the age, should have germline testing and serum testing.

That's a lot of alphabet soup to throw at you, but hopefully it gives you some perspective as you start to talk about this very important topic related to colon cancer. We can do better and certainly need to.

I'm Dr David Johnson. Thanks for listening.

David A. Johnson, MD, a regular contributor to Medscape, is 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 primary focus is the clinical practice of gastroenterology. He has published extensively in the internal medicine/gastroenterology literature, with principal research interests in esophageal and colon disease, and more recently in sleep and microbiome effects on gastrointestinal health and disease.

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