Multitarget Stool DNA Test Performance in an Average-Risk Colorectal Cancer Screening Population

Area of Science:

• Gastroenterology
• Oncology
• Molecular Diagnostics

Background:

• Colorectal cancer (CRC) screening is crucial for early detection and prevention.
• Multitarget stool DNA (MT-sDNA) tests offer a non-invasive approach to CRC screening.
• Fecal immunochemical test (FIT) is a common, less sensitive screening method.

Purpose of the Study:

• To evaluate the performance of an MT-sDNA test compared to FIT in an average-risk CRC screening population.
• To assess the sensitivity and specificity of MT-sDNA for detecting various colorectal lesions, including advanced adenomas.
• To compare the detection rates of high-risk advanced adenomas between MT-sDNA and FIT.

Main Methods:

• Prospective collection of 1,047 whole stool samples for MT-sDNA testing (KRAS mutations, NDRG4/BMP3 methylation, hemoglobin).
• Comparison of MT-sDNA results with FIT (various hemoglobin thresholds) for detecting CRC, advanced precancerous lesions, and non-advanced adenomas.
• Definition of high-risk advanced adenomas using DNA copy number events from low-pass whole genome sequencing.

Main Results:

• MT-sDNA demonstrated significantly higher sensitivity (46%) than FIT (27%) for advanced precancerous lesions (P < 0.001).
• Specificities were comparable: MT-sDNA (89%) and FIT (93%) for non-advanced/negative findings.
• MT-sDNA positivity correlated with multiple and larger lesions, and those with tubulovillous architecture.

Conclusions:

• MT-sDNA offers improved sensitivity for detecting advanced precancerous lesions in average-risk screening compared to FIT alone.
• Neither MT-sDNA nor FIT significantly enhanced the detection of high-risk advanced adenomas.
• MT-sDNA shows promise as a more sensitive non-invasive screening tool for colorectal neoplasia.