A comprehensive test menu explores genome for druggable targets to treat gastrointestinal cancers

Eye on Innovation

Last year in the U.S. there were an estimated 153,020 cases of colorectal cancer, which accounted for 7.8% of all new cancer cases. Since 1992, cases of colorectal cancer have been on a slow decline, yet 52,550 people died from it in 2023. At Mayo Clinic, a cutting-edge menu of both germline (inherited genetic alterations) and somatic (tumors due to non-inherited genetic alterations) testing are two critical tools helping to improve targeted treatments for colorectal and other common gastrointestinal (GI) cancers.     

One of the most innovative menu items is the MLH1 Hypermethylation germline test (Mayo ID: MLHPB), only offered at Mayo Clinic Laboratories where it was developed. From a blood specimen, this polymerase chain reaction (PCR) assay can detect if the MLH1 promoter is hypermethylated — a rare genetic condition where the MLH1 promoter gene gets “turned off,” meaning there's no gene product, or protein, that gets expressed. The loss of this gene puts a person at higher risk for a colon or endometrial tumor growth and confers a diagnosis of Lynch syndrome.

Every person has two copies of the MLH1 gene, and in cases of germline hypermethylation, one of them gets turned off.

Megan Hoenig, M.S., M.P.H., CGC

MLH1 is specifically called a ‘mismatch repair gene,’” says Megan Hoenig, M.S., M.P.H., a certified genetic counselor in Mayo’s Division of Laboratory Genetics and Genomics. “So if there's a mismatch in the DNA sequence, it would fix that mismatch, if the gene is on. But if a copy of the gene is off or if it is broken (i.e., a pathogenic variant occurs), then the body is not as good at repairing these mismatches, and progression to a tumor can occur.”

Another innovation in the laboratory is the liquid biopsy.

“In liquid biopsy, we are basically evaluating the shedding of the tumor DNA into the peripheral blood,” says Rondell Graham,M.B.B.S., a consultant in Anatomic Pathology at Mayo Clinic and a professor of laboratory medicine and pathology. “And we commonly will do that at diagnosis and on follow up. What we're doing is looking to see if there's any residual disease, post-treatment. The liquid biopsy, or other follow-up testing, can be really helpful to determine whether or not there's recurrence, which can facilitate the timing of intervention, and the selection of follow-up treatment.

“Our MLHPB test offers another option. This follow-up test is for a patient who has had a tumor with a loss of MLH1. We will do this test when we suspect that loss is due to a germline hypermethylation, which is uncommon.”  

Other somatic tests, like the BRMLH and ML1HM, look at the tumor tissue itself. “Both tests are used as follow-up to look for a pattern of MLH1 loss,” says Dr. Graham. “And that’s most commonly because of somatic hypermethylation in the MLH1 promoter. In colorectal cancer, it’s accompanied by BRAF mutations, and is the most common reason for loss of MLH1 gene.”

Searching the genome for druggable targets

In the context of somatic tumors, Mayo’s advanced test panels interrogate areas of the genome to look for “oncogenes,” which are genes that often mutate and thus have the potential to cause cancer. Oncogenes are among the most druggable targets, meaning they respond well to targeted cancer treatments.

Rondell Graham, M.B.B.S.

"Targeted testing for both germline and somatic GI cancers is what differentiates Mayo Clinic Laboratories from other reference labs in the country: it ultimately means better patient care and survival outcomes."   

“In terms of looking for druggable targets, we want to provide actionable information that allows the bedside physician to determine the most appropriate medication for the patient,” Dr. Graham explains. “Optimization of medication allows for the best kind of cost benefit ratio. So the healthcare resources are going into what therapies are most likely to work, rather than trying therapies that are unlikely to work. And that also has the potential to reduce toxicity. I think that actionable information helps with efficacy and cost-effectiveness.”   

Identification of a hereditary cancer syndrome also provides actionable information for both patients with cancer and their family members.

“Our testing can assess an individual’s cancer risk associated with more than 50 hereditary cancer predisposition syndromes,” says Wei Shen, Ph.D., a laboratory geneticist in Mayo’s Division of Laboratory Genetics and Genomics who specializes in hereditary cancers and germline testing. “Then, if the person is at risk, we can decide on a screening protocol to monitor them more diligently.”

Early bird gets the cure

For example, if a young person were to test positive for one of the genes known to cause Lynch syndrome (Mayo ID: LYNCP), the most common form of hereditary colorectal cancer, they could be started on colonoscopy screening much earlier, in their twenties, every one or two years. In this scenario, germline testing empowers the patient to know their risk level and, more importantly, catch cancer in the early stages if it develops.

Wei Shen, Ph.D.

“Cancer treatment is more likely to succeed if we can catch the cancer early enough,” says Dr. Shen. “So time is of the essence here, and early detection is a key for the efficacy of cancer treatment. And I think germline testing offers the opportunity for us to catch it early in the individuals who are at higher risk of developing cancer.” 

Individuals with Lynch syndrome have a higher risk of developing colon cancer and other GI cancers, such as stomach and small bowel. There is also a higher risk of developing endometrial, ovarian, and prostate cancer.

“That’s the unfortunate feature about these individuals who have cancer predisposition syndromes,” says Dr. Shen. “It’s not just one or two types of cancer. The patient is at higher risk for multiple cancer types and will need to be monitored for all of them.” 

The key distinction between somatic and germline testing

There is no risk of passing down somatic gene variants to the next generation. Conversely, germline variants are passed down about half the time. This is why, when a patient tests positive for a germline variant like Lynch syndrome, biological relatives all have a chance of carrying the same genetic alteration that will predispose them to cancer risk.

Negative test results can also be informative. On the germline side, a physician will often order genetic testing “to rule out a diagnosis or suspicion of something,” says Dr. Shen. “We can never completely rule out the possibility of genetic contribution, but with a negative result the possibility is much lower.”

Because Mayo Clinic is also a world-renowned hospital serving patients with both common and very rare GI cancers, the test menu takes advantage of this oncological expertise.

“We work very closely with our clinical colleagues here,” says Dr. Shen. “These are the physicians, the oncologists, the geneticists, who are taking care of cancer patients on a daily basis, and we can leverage their tremendous expertise to help us design those gene panels. So we look at multiple layers of information, including gene-disease associations, evidence on clinical treatments with the genes, and any other clinical management guidelines. We incorporate all this information in deciding on which gene we should include in our testing panels. And in our lab, we use multiple technologies — we mainly use NextGen sequencing, but we also have many other technologies that we can use to detect a genetic alteration that will be significant for a patient.”

Making sense of it all

Genetic counselors like Hoenig represent another area of expertise at Mayo. They are the critical link in helping patients navigate their test options when they want to explore their predisposition for GI cancers. Genetic counselors also help the patient and their physician make sense of all the information, both on the front- and back-end of testing, which would otherwise be daunting.

“Genetic testing is a dynamic field where there is constantly new knowledge and new literature about different genes,” says Hoenig. “That can be incredibly complex to someone who does not live and breathe that in their day-to-day. While we have oncologists who order our testing for hereditary GI cancers, we also have primary care providers who have to be on top of literally every organ system. Providers may have a question about what a test result means on a gene level, or if there's what's called a ‘variant of uncertain significance,’ or even which test to order. So we as genetic counselors are able to help explain all of those nuances.”

For Hoenig, what makes Mayo’s GI cancer testing menu further stand out is that it embodies a “one-stop shop.” She explains it this way: “We do both the tumor testing, whether that's large tumor panels like MCSTP, or just the tumor screenings like ML1HM, and we also have the germline testing, like our broad CRCGP test or our unique MLHPB. No other lab that I know of really has all of that in-house or in one facility.”   

Learn more about genetic testing available at Mayo Clinic Laboratories.

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Chris Bahnsen

Chris J. Bahnsen covers emerging research and discovery for Mayo Clinic Laboratories. His writing has also appeared in The New York Times, Los Angeles Times, and Smithsonian Air & Space. He divides his time between Southern California and Northwest Ohio.