DNA Methylation Analysis in Stool Samples for Screening of Lynch Syndrome-Associated Colorectal Cancer

Colorectal cancer (CRC) is a malignant disease with a high incidence and mortality rate worldwide. Globally, more than 1 million new cases of CRC are diagnosed annually, and approximately 600,000 patients die from the disease each year. In China, CRC has the third-highest incidence, following lung and stomach cancers and the fifth-highest mortality rate. With changes in lifestyle and an aging population, the incidence and mortality rates of CRC in China have been continuously rising. About 30% of colorectal cancer (CRC) patients exhibit a hereditary predisposition, including familial adenomatous polyposis (FAP) and Lynch syndrome. Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC), is the most common hereditary colorectal cancer, accounting for 3%-5% of CRC cases. Several clinical criteria, such as the Amsterdam Criteria and Bethesda guidelines, are applied to the diagnosis of Lynch syndrome. Effective diagnosis, screening, and prophylactic surgery for Lynch syndrome can significantly reduce colorectal cancer mortality by 7%-42%, as well as mortality from endometrial and ovarian cancers by 1%-6%. Intensive screening measures are critical for patients with Lynch syndrome, who are considered to be at high-risk for CRC.

Due to the lack of early symptoms, many CRC patients are diagnosed at the middle to late stages of the disease, which places significant financial pressure not only on the patients themselves but also on society and their families. Screening is one of the most effective tools for preventing colorectal cancer and can reduce mortality by more than 50%. In developed countries such as the United States, the United Kingdom, and Japan, colorectal cancer screening has been integrated into public health programs, highlighting its critical role in disease prevention. Currently, colorectal cancer screening relies on the fecal occult blood test, followed by detailed examinations such as colonoscopy in our country, which still presents several challenges. First, the sensitivity of the fecal occult blood test is insufficient, leading to a high rate of underdiagnosis. Second, colonoscopy is an invasive procedure with relatively low acceptance among patients. Furthermore, colonoscopy is typically performed in a facility-based setting, which requires advanced endoscopic equipment and experienced endoscopists, making it highly dependent on medical resources. Given the limited healthcare resources, achieving universal coverage of the entire population with a facility-centered colonoscopy model is challenging, resulting in a low overall screening rate. Improvements are needed to enhance the efficiency and coverage of screening programs to better prevent and control the incidence of CRC. For patients with Lynch syndrome, intensive colonoscopy may lead to poor compliance due to its tedious process. To address these challenges, we propose to replace part of the colonoscopy screening with DNA methylation testing for fecal samples. Self-sampling methylation screening for colorectal cancer in patients with Lynch syndrome could not only alleviate the excessive strain on healthcare resources but also improve patient compliance with screening.

To explore the optimal screening strategy, reduce the frequency of colonoscopy, and improve patient compliance, we propose conducting methylation screening alongside colonoscopy for patients with Lynch syndrome. This study will include three consecutive rounds of head-to-head methylation screening, with colonoscopy as the control, involving 400 patients with Lynch syndrome. We aim to identify new screening criteria for this high-risk group, reduce the frequency of colonoscopy, improve screening compliance, and ultimately reduce the incidence of colorectal cancer in these patients.