Researchers at The University of Texas MD Anderson Cancer Center have discovered a new blood-based biomarker that can help identify and characterize asymptomatic people with Lynch syndrome who are more susceptible to developing cancer based on early immune detection signatures, allowing clinicians to stratify patients based on their personal risk level.
The study, published by Deng et al in Nature Communications, was led by Eduardo Vilar-Sanchez, MD, PhD, Chair Ad Interim of the Department of Clinical Cancer Prevention at MD Anderson. The results advance the understanding of T-cell responses in Lynch syndrome carriers, potentially providing personalized insights for early cancer detection, monitoring, and therapeutic interventions for these individuals.
“Providing a potential noninvasive blood test to track cancer risk and immune activity in patients with Lynch syndrome is a tremendous step forward for this patient population,” Dr. Vilar-Sanchez said. “These are valuable insights into immune responses that can help personalize the way we monitor and direct prevention strategies."
Study Background
Lynch Syndrome is a hereditary condition involving mutations in the germline of DNA mismatch repair genes. People with Lynch syndrome have a genetic predisposition to develop cancers with microsatellite instability, especially colorectal and endometrial cancers, and they often develop cancers at a younger age than the general population. Having a way to understand an individual’s level of risk for developing cancer could help clinicians offer appropriate surveillance and intervention to improve outcomes.
These microsatellite mutations, which result in insertions or deletions of DNA sequences, also create tumor-specific neoantigens. These neoantigens are protein fragments on cancer cells that T cells recognize as foreign, triggering an immune response.
Study Methodology and Findings
The researchers sequenced T-cell receptors (TCR), which help T cells identify and attack threatening neoantigens on cancer cells.
They characterized the TCRs found in peripheral blood mononuclear call (PBMC) samples—which contain crucial T cells involved in immune defense—from 277 people, including 102 survivors of Lynch syndrome, 130 carriers without a history of cancer (previvors), and 45 controls without Lynch syndrome or cancer. They also performed TCR sequencing in the colorectal tissues of 3 cancers and 11 precancers matched to those PBMC samples.
In colon tumors and precancer tissues, certain T cells—identified by their corresponding TCRs—were expanded in response to these tumor-specific neoantigens. Up to 41% of the expanded TCRs from colon precancers and tumors were detected in Lynch syndrome carriers but not in people without Lynch syndrome, suggesting that the immune system is surveilling and responding to early signs of cancer.
The researchers then used this data to generate a classification model that distinguishes Lynch syndrome carriers from control samples simply by looking at the TCR patterns in blood. This model helped identify Lynch syndrome carriers, independent of cancer history, along with cancer-free Lynch syndrome previvors.
The study found that circulating cancer-associated TCRs can be identified in blood samples from Lynch syndrome carriers, providing unique immune signatures that could detect individuals at higher risk of cancer development. While further validation is needed, this blood-based biomarker could serve as a noninvasive tool for early detection, risk assessment, and personalized surveillance for patients with Lynch syndrome.
DISCLOSURE: For full disclosures of the study authors, visit nature.com.
