IDDF2024-ABS-0362 Dopamine receptor 4 hypermethylation: a multi-malignant tumor marker plausible for colorectal cancer screening through fecal DNA testing

<h3>Background</h3> Dopamine receptor 4 (DRD4) hypermethylation in colorectal cancer has been found in epigenomic studies, but it has not yet been evaluated as a potential methylation marker for colorectal cancer screening. <h3>Methods</h3> Multiple types of cultured human cancer cells, matched cancer and normal tissues, colorectal neoplastic lesions (paraffin-embedded), as well as peripheral blood samples, were tested for DRD4 gene promoter hypermethylation by a pyrosequencing-validated Meth Light method. Fecal DNA samples from the community population in a colorectal cancer screening program were collected and tested. The diagnostic potential of the marker for advanced colorectal neoplasia was evaluated using colonoscopy as the reference standard. <h3>Results</h3> DRD4 hypermethylation was intensely presented in 26 types of human cultured cancer cells and 7 types of cancer tissues (the highest in pancreatic cancer, 92.31%), but none in a blood sample (n=327), an osteosarcoma MNNG-HOS cell line sample and six gastrointestinal stroma samples. For the tissue DNA from paraffin-embedded samples, DRD4 hypermethylation was detected in 70.00% (95% CI=49.92-90.08, n=20) of colorectal carcinoma, 48.28% (95% CI=30.09-66.46, n=29) of advanced adenoma, 13.95% (95% CI=10.04-17.87, n=301) of non-advanced adenoma, 28.57% (95% CI=11.84-45.30, n=28) of serrated adenoma, 19.70% (95% CI=10.10-29.29,n=66) of hyper plastic polyp and 9.52% (95% CI=-3.03-22.08, n=21) of inflammatory polyp. The positive rate of DRD4 hypermethylation in the fecal DNA with a qualified quantity (&gt;1ug in total) was 5.85% (95% CI=3.78-7.91, n=496). The positive predictive value, sensitivity and specificity for detecting advanced colorectal neoplasia were 31.03% (95% CI=14.20-47.87), 17.31% (95% CI=8.23-30.33) and 95.50% (95% CI=93.13-97.23). <h3>Conclusions</h3> DRD4 hypermethylation is a multi-malignancy tumor marker, which might be specific to epithelial cancer. Detecting DRD4 hypermethylation in fecal DNA has a high positive predictive value and high specificity for advanced colorectal neoplasia, but the sensitivity needs to be improved.