Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC), is an inherited genetic disorder that significantly increases an individual’s risk of developing various types of cancer. Lynch syndrome is the most common inherited cause of colorectal cancer (cancer of the colon or rectum) and endometrial cancer (cancer of the lining of the uterus). In individuals with Lynch syndrome, 30% to 74% of patients will develop colorectal cancer, while 28% to 60% of women will develop endometrial cancer. These elevated rates demonstrate the importance of early detection and preventive strategies in Lynch syndrome patients.
Molecular Basis of Lynch Syndrome
Lynch syndrome is caused by inherited mutations in genes responsible for repairing errors that occur during DNA replication, which is when cells copy their DNA. These genes are part of the DNA mismatch repair (MMR) system, which fixes small mistakes that arise during cell division. The most common MMR genes affected by Lynch syndrome are MLH1, MSH2, MSH6, and PMS2 genes.
When these genes are mutated, the DNA repair process is damaged, leading to an accumulation of errors. This condition is known as microsatellite instability (MSI), which describes changes in short, repeated sequences of DNA particularly prone to copying errors. Over time, these errors can result in frameshift mutations, which alter how genetic information is read and interpreted by the cell.
These mutations may also lead to the production of abnormal proteins known as neoantigens. Neoantigens are antigens, or particles that can trigger an immune response, formed from cancerous tumors. As a result, tumors that develop in the absence of functioning MMR genes (deficient MMR or dMMR tumors) often carry a high neoantigen load, making them more visible to the immune system and potentially more responsive to certain types of treatment.
Current Treatments and Emerging Research
Managing Lynch syndrome involves a combination of surveillance, preventive measures, and genetic counseling for early detection and prevention of cancer. Regular colonoscopies starting in early adulthood (typically by age 20–25) and repeated every one to two years allow for the detection and removal of precancerous growths before they become malignant–cancerous. Higher risk patients undergo prophylactic surgery (preventative surgery to remove tissues before they become cancerous), including hysterectomy (removal of the uterus) or colectomy (removal of the colon), to reduce cancer risk. Methods such as genetic counseling are also crucial strategies for early detection. Family members of an individual diagnosed with Lynch syndrome are encouraged to undergo testing to determine if they too have inherited mutations that cause Lynch syndrome.
In recent years, researchers have explored whether immunotherapy, a treatment that uses the body’s immune system to fight disease, could prevent cancer in high-risk patients with Lynch syndromeA study led by investigators at Memorial Sloan Kettering Cancer Center evaluated the use of immune checkpoint blockade (ICB) in Lynch syndrome patients who did not have detectable cancer at the time of treatment. Researchers hypothesized that ICB might help the immune system eliminate or suppress early cancer development. Immune checkpoint inhibitors are drugs that block specific proteins cancer cells use to evade detection by the immune system. These proteins, or “checkpoints,” act like brakes on the immune response. By blocking them, ICB therapy allows T cells, a white blood cell that fights infections and tumors, to recognize and attack abnormal cells more effectively.
In a study cohort of 172 Lynch syndrome patients treated with immune checkpoint blockade (ICB) drugs, 21 patients (12%) developed new malignancies after receiving ICB treatment, while the other 88% did not. 91% of these malignancies were MMR-deficient tumors, which is consistent with what is typically observed in Lynch syndrome. The median time to cancer development post-treatment was 21 months. Additionally, among patients who underwent a surveillance colonoscopy following treatment, researchers observed a 39% (24 patients) detection rate of premalignant polyps, or abnormal growths that can potentially turn into cancer if left untreated.
Immune checkpoint inhibitors are drugs that block specific proteins cancer cells use to evade detection by the immune system. These proteins, or “checkpoints,” act like brakes on the immune response. By blocking them, ICB therapy allows T cells–a type of white blood cell that fights infections and tumors–to recognize and attack abnormal cells more effectively.
Since the tumors in Lynch syndrome carry a high neoantigen burden, researchers hypothesized that ICB might help the immune system eliminate or suppress early cancer development. In a study cohort of 172 Lynch syndrome patients treated with immune checkpoint blockade (ICB) drugs, 21 patients (12%) developed new malignancies after receiving ICB treatment, while the other 88% did not. 91% of these malignancies were MMR-deficient tumors, which is consistent with what is typically observed in Lynch syndrome. The median time to cancer development post-treatment was 21 months. Additionally, among patients who underwent a surveillance colonoscopy following treatment, researchers observed a 39% (24 patients) detection rate of premalignant polyps, or abnormal growths that can potentially turn into cancer if left untreated.
When comparing cancer rates before and 21 months after ICB treatment, researchers found that the overall rate of tumor development remained largely unchanged. However, subgroup analyses revealed a decreased incidence of post-ICB visceral tumors (tumors affecting internal organs), suggesting that while ICB may not eliminate the risk of cancer, it might reduce the occurrence of more dangerous tumor types.
Future Directions
The use of ICB offers a promising new approach to cancer prevention in individuals with Lynch syndrome. While current strategies focus on surveillance and surgery, ICB harnesses the immune system to target abnormal cells early, potentially reducing the risk of dangerous tumor development. Although further studies are needed to determine the safety and efficacy of the treatment, early findings suggest that ICB could complement existing prevention methods. In the future, ICB may transform the focus of hereditary cancer risk from early detection and surveillance to proactive treatments that could significantly improve the lives of patients.
References
https://www.nature.com/articles/s41591-023-02544-9
https://pmc.ncbi.nlm.nih.gov/articles/PMC10252762/
https://pubmed.ncbi.nlm.nih.gov/36706841/
https://pubmed.ncbi.nlm.nih.gov/30848956/
https://pmc.ncbi.nlm.nih.gov/articles/PMC9954007/
