Research Highlights: Looking Deep into Genetic Changes that Increase Colorectal Cancer Risk to Prevent or Detect Inherited Cancers

Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC), is the most common inherited genetic change that increases the risk of several kinds of cancer including colorectal cancer. About 3% of all colorectal cancers in the United States occur in people with these inherited genetic changes; more than 1 million people in the U.S. have this syndrome.

Those with Lynch syndrome inherit changes in the DNA mismatch repair genes (MMR genes), which normally correct mistakes made during cell division when a cell duplicates its complete set of DNA. This results in errors in the replication of microsatellite DNA resulting in too few or too many bases in the repeated sections. This is called microsatellite instability or MSI. Since genes code DNA in sets or frames of threes, an altered or incorrect number of bases means that when proteins are made from this altered code, the ‘frame’ that is read is now wrong; this is called frameshift mutation.

People with Lynch syndrome have a 50% to 80% lifetime risk of colorectal cancer, a 40% to 60% lifetime risk of endometrial cancer, and increased risk of other cancers as well.

These two studies are looking at how these genetic changes might be used to find ways to prevent cancers in those with Lynch syndrome by vaccine or to monitor people with the inherited changes without having to do frequent colonoscopies.

Many cancers that occur in people without Lynch syndrome also have changes in MMR genes and they also show MSI, meaning that successes for people with this inherited risk may lead to prevention and detection methods for many more people.

Looking for a Vaccine Target

In this study, researchers from the University of Texas M.D. Anderson Cancer Center carried out genomic analyses of colon tissues from people with Lynch syndrome, looking for alterations that happened during the initial changes from healthy tissue to developing cancer. They obtained samples from people with Lynch syndrome that represented precancerous changes, advanced precancerous changes, early-stage cancer, and some tissues that had no potential to become cancer.

From these tissues, they generated a catalog of shared and recurrent novel frameshift proteins (neoantigens) expressed on these cells due to the mutations that occur. These neoantigens may be used to create a vaccine, which if successful, can induce antitumor immunity and protect Lynch syndrome-affected individuals from developing cancers.

Previous genomic research had been done to identify these frameshift neoantigens in cancers that occur in people with Lynch syndrome, but this study included precancers, hence, identifying changes that can be used to design preventive vaccines. Additional research will be done to test the identified antigens using other patient samples and in animal models of Lynch syndrome.

Reference: Bolivar AM, Duzagac F, Deng N, Reyes-Uribe L, Chang K, Wu W, Bowen CM, Taggart MW, Thirumurthi S, Lynch PM, You YN, Rodriguez-Pascual J, Lipkin SM, Kopetz S, Scheet P, Lizee GA, Reuben A, Sinha KM, Vilar E. Genomic Landscape of Lynch Syndrome Colorectal Neoplasia Identifies Shared Mutated Neoantigens for Immunoprevention. Gastroenterology. 2024 May;166(5):787-801.e11. doi: 10.1053/j.gastro.2024.01.016. Epub 2024 Jan 18. PMID: 38244726; PMCID: PMC11034773.

A Possible Blood Test Instead of Multiple Colonoscopies

As noted earlier, deficient DNA MMR leads to the accumulation of frameshift neoantigens, which are thought to play a role in the increased immune response of cancers associated with the syndrome, but have not been used by themselves to identify people at risk. People with Lynch genetic mutations have to undergo frequent colonoscopies, beginning as young as age 20, to check for possible abnormal growths, polyps, or cancer. Researchers were looking to identify a biomarker panel similar to other ‘liquid biopsy’ assays, to better identify the optimal timing when to start monitoring people with Lynch syndrome.

A frameshift mutation-based biomarker panel was developed and validated using samples from colorectal cancers that showed microsatellite instability. Then specific mutation targets were selected and tested against samples of cancer, adjacent normal tissue, and in blood from 45 people with Lynch syndrome. The researchers also looked at samples from 84 healthy people to rule out common changes that would not signify cancer.

These researchers showed that frameshift mutations can be detected in blood and used to monitor disease via a blood test in people with Lynch syndrome. Measuring these frameshift mutations over time could be a strategy to surveil Lynch syndrome carriers to identify when or how often to do colonoscopy. The investigators were from the National Cancer Institute, Roswell Park Cancer Center, Weill Cornell Medicine, and the University Hospital Heidelberg.

Because this study was done from samples retrospectively, the next step is to look at this biomarker panel in a prospective study.

Reference: Song Y, Loomans-Kropp H, Baugher RN, Somerville B, Baxter SS, Kerr TD, Plona TM, Mellott SD, Young TB, Lawhorn HE, Wei L, Hu Q, Liu S, Hutson A, Pinto L, Potter JD, Sei S, Gelincik O, Lipkin SM, Gebert J, Kloor M, Shoemaker RH. Frameshift mutations in peripheral blood as a biomarker for surveillance of Lynch syndrome. J Natl Cancer Inst. 2024 Jun 7;116(6):957-965. doi: 10.1093/jnci/djae060. Erratum in: J Natl Cancer Inst. 2024 Jul 26:djae174. doi: 10.1093/jnci/djae174. PMID: 38466935; PMCID: PMC11160491.