Germline Testing for Lynch Syndrome: More Important Than Ever


With the emergence of several targeted treatments that have shown efficacy in individuals with germline pathogenic variants, specifically in DNA mismatch repair, the need for germline genetic testing has become even more pronounced.

With the emergence of several targeted treatments that have shown efficacy in individuals with germline pathogenic variants, specifically in DNA mismatch repair, the need for germline genetic testing has become even more pronounced, according to Elena M. Stoffel, MD, MPH. Results could lead to the identification of Lynch syndrome and other hereditary cancer syndromes associated with the risk of developing colorectal cancer (CRC) and other diseases.

“We [have] information on the importance of assessing for Lynch syndrome: How to test people for Lynch syndrome, how to treat Lynch-associated cancers, and how to prevent cancers in Lynch syndrome,” said Stoffel. “However, really being able to translate [what we learn] from the studies into clinical [practice] and the care for patients is really where we are now. Building the awareness, developing the systems, and providing the education to both providers and patients is [what is needed].

One study led by investigators at Memorial Sloan Kettering Cancer Center enrolled 15,405 patients with Lynch syndrome pan-cancer with microsatellite instability—high (MSI-H) and MSI-indeterminant tumors.

The MSK-IMPACT next-generation sequencing platform was used to identify Lynch syndrome in 16.3%, 1.9%, and 0.3% of patients with MSI-H, MSI-indeterminate, and microsatellite-stable tumors, respectively (P < .001). The study also indicated that Lynch syndrome extends beyond CRC and endometrial cancers and affects numerous other tumor types, including urothelial cancers, ovarian cancers, specific sarcomas, and several other hypermutated tumors, Stoffel added.

“What we were diagnosing as Lynch syndrome, historically, was probably just the tip of the iceberg. Many more patients are out there with Lynch syndrome who remain undiagnosed,” explained Stoffel. “The potential of making that diagnosis, not only for the treatment of patients with cancer, but also for the cancer prevention in their family members is really important.”

In an interview with Oncology Nursing News' sister publication, OncLive, during the 2020 Institutional Perspectives in Cancer webinar on Precision Medicine, Stoffel, an associate professor at Michigan Medicine, University of Michigan, further discussed the importance of genetic testing in detecting Lynch syndrome and other hereditary syndromes associated with risk of CRC and other cancers.

OncLive: What has been learned in recent years with regard to germline testing for Lynch syndrome cancers?

Stoffel: [Results from] many of the published studies have told us that the number of patients who carry germline alterations associated with genetic predisposition is actually much higher than we previously thought. The clinical presentations of some of these patients can be very different from what has been described in the original papers. Now, we know that Lynch syndrome, which is one of the most common hereditary cancer syndromes, has a population prevalence of about 1 in 300. Many patients who develop Lynch syndrome cancers could be identified if we broaden our search for these germline mutations. Given recent advances in therapy for hypermutated tumors, this is especially relevant in both cancer treatment and also prevention in these affected families.

Do any barriers to genetic counseling or germline testing exist for Lynch syndrome?

Barriers exist on multiple levels. First, the patient's physician or clinician needs to consider the possibility of Lynch syndrome, because if they don't think about that, they’re going to miss the diagnosis.

Secondly, although there are recommendations for universal tumor testing for colon and endometrial cancers, many clinical sites don't have access to testing tumors for dMMR. That universal screening only gets applied at centers where they have the pathology resources available. Thirdly, even when the providers have identified the need for genetic testing, being able to convey the importance of that to patients and make it easier for them to seek genetic evaluation remains a barrier.

Fortunately, over the past few years, many more insurances are covering genetic testing; the cost of testing has [also] decreased. Additionally, new models for accessing genetic services exist so patients no longer have to travel to a genetic specialty clinic. In many cases, providers can order the testing themselves if they're comfortable with that. They can also refer [their patients] to telehealth services, which are trying to improve access to genetic testing. [However], a patient has to be motivated to seek out that extra testing. Our ability to explain to patients why this information is important is really the key to improve access to genetic testing.

How should genetic testing be approached in a clinical practice? When should this testing take place in the treatment journey?

We can think about this in different ways. In an oncology practice, ASCO has recommended that, at the basic intake appointment, the clinician obtain a family history from patients that includes cancer diagnoses, as well as dates and ages of diagnoses for all first- and second-degree relatives. The goal of that should be to prompt the question: How likely is it that this patient's tumor developed in the context of a genetic predisposition syndrome?

If the answer to that is possibly or likely, then a discussion should take place in terms of further evaluation. For many tumor types now, testing tumors has become a part of the treatment pathway. Certainly, being able to identify whether tumors are hypermutated and whether tumors have dMMR should also be [done] early on in the treatment algorithm, as well as the diagnostic evaluation for hereditary cancer syndromes.

Now that many targeted treatments have emerged as being particularly effective in individuals who have germline pathogenic variants, specifically in DNA mismatch repair or in double-stranded DNA repair, germline genetic testing should be part of the discussion at the first intake when patients are discussing what possible treatments are in store for them.

Could you discuss the importance of testing MSI-H patients for Lynch syndrome?

Approximately 15% to 30% of all colon cancers are MSI-H. Of all colon cancers, about 3% correspond to Lynch syndrome. For several years now, universal tumor screening for dMMR has been recommended as a best practice. Doing universal tumor testing is 1 thing; following up on all those results is another. When a patient has colon cancer, what’s the mismatch repair status of the cancer? If it's dMMR, has this patient been evaluated for the possibility of Lynch syndrome? Making this part of our systematic checklist is an important way to proceed.

What studies are particularly important in this field?

First of all, Matthew Yurgelun, MD, of Dana-Farber Cancer Institute, [has a] study that was published in the Journal of Clinical Oncology and demonstrated that of all unselected CRCs, approximately 10% carry germline pathogenic variants. Of those, Lynch syndrome is the most important group of genes involving the DNA mismatch repair genes. However, other genes are there as well, including genes associated with hereditary breast and ovarian cancer, or BRCA genes. BRCA1/2 and PALB2 emerge in some individuals with CRC. It just goes to show that there is overlap among the different hereditary predisposition syndromes with regard to cancer development and risk.

Another important study was [conducted at the University of Michigan] and the Ohio State University Comprehensive Cancer Center—James. Results showed that among unselected individuals with colon cancer diagnosed at an age under 50 years, the prevalence of germline mutations is about 20%; this translates to about 1 in 5 [patients]. As such, it’s particularly important to offer germline genetic testing to that group.

Finally, the group from Memorial Sloan Kettering Cancer Center looked at the prevalence of Lynch syndrome among hypermutated tumors, which basically shows us that the spectrum of cancers associated with Lynch syndrome goes beyond CRC and endometrial cancers, which are the 2 hallmark cancers. It also extends to urothelial cancers, ovarian cancers, certain sarcomas, and several other tumors for which the diagnosis of Lynch syndrome would not have necessarily been considered, except for the fact that these tumors are hypermutated and look very different from other tumors in their group.

As with most [findings] in oncology, once there is a therapeutic implication, that tends to gain traction; even though we've known that diagnosing Lynch syndrome makes a big difference for the care of [patients with] cancer and family members, the fact that it can actually influence our treatment algorithms now makes it really important to address up front.

What significant clinical challenges remain in implementing genetic testing?

From the provider end of things, many are uncomfortable with genetic testing to the point where they're uneasy discussing it with patients because they don't have the familiarity with the process for diagnostic testing or for the interpretation of genetic test results. The more we can educate our clinical providers in what genetic testing is and why it's important, the easier it's going to be to talk to patients about it, and the more patients are going to recognize the importance of getting tested.

What is your take-home message regarding genetic testing?

For every patient we see, we should consider the likelihood that the cancer was the result of a hereditary cancer syndrome and what can be done to figure that out. Now that tumor testing has become a part of many of our treatment algorithms, that provides us with a great opportunity to be able to look for the tumor phenotypes. We can also do a better job of taking family histories from patients and think about the pattern of cancer in the family, and [whether it points to the] possibility of an underlying genetic predisposition. If we think about it, then we're less likely to miss it.


Latham A, Srinivasan P, Kemel Y, et al. Microsatellite instability is associated with the presence of lynch syndrome pan-cancer. J Clin Oncol. 2018;37(4):286-295. doi:10.1200/JCO.18.00283

This article was originally published on OncLive as, "Stoffel Underscores Importance of Germline Testing for Lynch Syndrome."

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