Researchers Track the Memory of Cancer in Lynch Syndrome

For Eduardo Vilar-Sanchez, MD, PhD, the road to a new blood-based biomarker for cancer risk started with a basic question: how does colorectal cancer actually begin?

"I am a physician-scientist and a medical oncologist by training, so I have been faculty at MD Anderson for the past 14 years," said Vilar-Sanchez, who joined MD Anderson after his fellowship at the University of Michigan. "I have always been very interested in colorectal cancer in general, so when I joined the Department of Clinical Cancer Prevention to launch my research group, our main focus was to understand how colorectal cancer started.”

That meant going further upstream than most cancer research dares to go: not studying tumors after they form but watching the normal lining of the colon transform into something dangerous. "It was critical to understand and examine how the normal colorectal epithelium, the normal lining of our colon, transforms into premalignant lesions, which we now know as precancer," he explained in an interview with Targeted Oncology.

To do it, Vilar-Sanchez borrowed tools typically reserved for treating cancer, not preventing it. "What I did, as a medical oncologist and a molecular biologist interested in cancer biology, was to borrow all the tools that we have been applying to the world of therapeutic medical oncology," he said. "We applied next-generation sequencing and genetic mouse models—instead of focusing on the transformation of precancers into cancers, we wanted to focus on the normal into precancer." The goal, he said, was to identify targets and push toward what's now called cancer interception—catching disease before it's disease at all.

That search eventually led him to one of the most aggressive natural experiments in oncology: hereditary colorectal cancer syndromes.

Why Lynch Syndrome?

"To understand the larger question, which is how colorectal cancer happens in the general population, we need to go to the extremes," Vilar-Sanchez said. People born with certain inherited genetic mutations face a dramatically higher lifetime risk of developing colon cancer. The general population's lifetime risk hovers around 5%. For people with Lynch syndrome, he notes, that number can climb to 80%, depending on which gene is mutated.

That stark difference is precisely what makes Lynch syndrome carriers so valuable to study. "For us, it's an opportunity to examine how colorectal carcinogenesis happens in an accelerated way," Vilar-Sanchez said. It's also, he added, "an opportunity to engage with a community...that is in need to find tools to early diagnose cancer and to intervene." MD Anderson's role as a large tertiary referral center has only deepened that opportunity. "Our population of Lynch syndrome carriers has been growing for decades, so we have access to tissues and blood that the patients very kindly donate to us."

What the Immune System Already Knows

The study, published in Nature Communications, set out to answer a question nobody had systematically tackled before: What has the immune system of a Lynch syndrome carrier actually learned over a lifetime of growing—and removing—precancerous lesions?¹

It's a question rooted in basic biology. Lynch syndrome is caused by inherited mutations in DNA mismatch repair genes, and tumors that arise from this defect are riddled with errors that create what researchers call neoantigens—abnormal protein fragments that look foreign to the immune system. T cells, the immune system's targeted attack force, are built to recognize exactly these kinds of red flags.

"This is the first time that somebody tried to get a look into what the immune system has been recognizing in this patient population," Vilar-Sanchez said. "It is very pertinent, because as it's already known, Lynch syndrome carriers have a hyperactivated immune system, and this is because of the type of lesions, precancers, and tumors that they grow; these tumors and lesions have an abundance of mutated proteins.”

His hypothesis: years of growing and surgically removing polyps and precancerous lesions during routine colonoscopies have effectively been training the immune system all along, even when no cancer ever develops. "Over the lifetime of Lynch syndrome carriers, the immune system has been somehow getting all the input from all the precancers that they have been growing, and then they go to colonoscopy, and they remove them, but all of that exposure is somehow teaching an immune system, and nobody has systematically looked into that."

To test it, the team sequenced T-cell receptors—the molecular sensors T cells use to identify threats—in blood samples from 277 people: 102 Lynch syndrome survivors who had been diagnosed with cancer, 130 "previvors" who carry the mutation but have never had cancer, and 45 people from the general population with no Lynch syndrome and no cancer history. "We sequenced the T cells in the circulating blood of the cohort of Lynch syndrome carriers with a cancer history and without a cancer history—that's what we call previvors and survivors," Vilar-Sanchez explained.

The results were clear enough to function almost like a fingerprint. "Lynch syndrome survivors display a wide range of clones in their T cells that basically are subsequent to recognizing and being exposed to cancer, and at the point that if you will just take a drop of the blood of a Lynch syndrome carrier without knowing that it's a Lynch syndrome carrier, you will be able to tell distinctively that that person has had Lynch syndrome," he said. The team used this data to build a classification model that could distinguish Lynch syndrome carriers—survivors and previvors alike—from the general population using nothing but a blood draw.

"We got a biological window into the immune response of the Lynch syndrome carriers," Vilar-Sanchez said, "and the translational application of that is the development, hopefully in the future, of biomarkers to track whether or not there is cancer growing in Lynch syndrome carriers."

Matching Blood to Tumor

The second major finding came from a more targeted comparison: matching T-cell receptors found in a patient's blood directly against T-cell receptors found in that same patient's tumor or precancerous tissue. Researchers performed this paired analysis on tissue from 3 colorectal cancers and 11 precancers matched against the corresponding blood samples.

"We wanted to know if the immune system was learning—if it was recognizing and creating specific defenses…against those lesions, the tumors and the precancers," Vilar-Sanchez said. "By doing a comparison and trying to see what the match between clones is…we also had a biological window into the type of recognition that the immune system is exerting on those lesions."

The numbers were striking. "When you compare the T cells in tumors in colorectal cancers from Lynch syndrome carriers and blood, of the top 100 T-cell receptors that you identified in the tumor, you identified [up to 41%] of those already in blood," he said.

What surprised him more was that the same held true even before a lesion became cancer. "For a long time, people were saying that precancers, because they are not tumors, are not invasive. The immune system is not even learning or being exposed to all of those," Vilar-Sanchez says. "It resulted that when we analyzed again the precancer—the polyps from the colonoscopy—and the blood, 28% of the T-cell receptors that are in the polyps were already in the blood." In other words, the immune system appears to be mounting a detectable response even at the earliest, noninvasive stage of disease—long before a polyp would ever be called cancer.

"Again, that highlights the potential to use this technology, T-cell receptor sequencing, for monitoring what's going on over the lifetime of these patients," he said, "and hopefully at some point articulate this into a tool for early diagnosis and immune surveillance." He added that the approach is already being explored in active vaccine research: "There are also implications now that we are doing vaccine development of using these tools as well to track how vaccines boost the immune system response."

From the Lab to the Clinic

Looking ahead, Vilar-Sanchez said that the next step in this research is the work of translation. "I think the task ahead of us is to understand well how we can use this technology and this knowledge in clinical practice," he said. "Now that we have been able to establish a profile, now that we have been able to provide a proof of principle that you get this biological window by looking into the circulating immune system, can we effectively apply that to immune surveillance?"

He described what that might look like in his own clinic. "My dream would be that one of my patients that comes every Wednesday to the clinic with Lynch syndrome, I am able to sample their blood and I can tell them whether or not they have specific clones that might be alerting me of whether or not there is something growing—or, if they participate in a clinical trial, whether or not the vaccine that we have applied is boosting the immune response against potential T-cell receptor clones that are going to take care of tumors."

There will be technical hurdles along the way, he acknowledged, but he framed the larger mission plainly. "I think that is the real prize—how we apply this and how we serve patients so they can live longer, healthier, and cancer-free lives."

REFERENCE

1. Deng N, Duzagac F, Bolivar AM, et al. Genomic analysis of T Cell receptors reveals lynch syndrome specific immune signatures. Nat Commun. 17, 4790 (2026). doi:10.1038/s41467-026-71243-z