The sequence & timing of cancer development in LS: paving the way for cancer prevention strategies

Sanjeevani Arora – CGA-IGC Research Committee

Lynch syndrome (LS) is characterized by Mismatch Repair (MMR) deficiency, which increases the risk of colorectal, endometrial, and other cancers. MMR deficiency occurs due to germline mutations in MMR genes or somatic epigenetic silencing of MLH1, resulting in errors when DNA is copied in the cells. However, the relationship between MMR deficient crypt foci (MMR-dcf) and cancer initiation in LS and their interaction with the immune system are not well understood.

To address this knowledge gap, Dr. Kevin Monahan, from St. Mark’s Hospital and Imperial College in the United Kingdom, and colleagues conducted a study to investigate the early interactions between the MMR-dcf and the immune microenvironment in the bowel of LS patients. Their findings were presented at the Collaborative Group of the Americas on Inherited Gastrointestinal Cancers (CGA-IGC) Annual Meeting on November 12th 2022, in Nashville, TN.

They analyzed normal tissue samples from 32 confirmed LS patients, including 13 normal LS colon without cancer, 13 normal LS colon with distant cancer, and 13 adenoma adjacent normal tissue samples. They used immunohistochemical staining to identify the frequency and location of MMR-dcf and multiplexed, whole-slide cyclic immunofluorescence (CyCIF) to characterize the immune microenvironment around MMR-dcf.

Their results showed that MMR-dcf were more prevalent in adenoma adjacent tissue than in other areas of LS bowel. The CyCIF analysis found that MMR-dcf have increased infiltration of cytotoxic T-cells and decreased Treg cells. The study provides new insights into the early interactions between MMR-dcf and the immune system in LS patients and highlights the importance of further research in this area.

Dr. Kevin Monahan explained, “The sequence and timing of events leading to cancer development in Lynch syndrome may provide opportunities for cancer prevention. These events include molecular alterations, and the interaction with the immune system, and the insight that this understanding provides may indicate why some pre-cancerous change progresses while others do not. In our work, we examined tissue biopsies from around colon cancer and polyps. We worked out the type and the quantity of immune cells in these regions of the colon and identified changes to DNA within the cells. In the future, we hope that this work will contribute to the development of new therapies that can take advantage of our immune system to prevent cancer development, for example, if we predict those people with Lynch syndrome who may be at higher risk of developing cancer in future and offer them personally-designed colonoscopy schedules.”

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