Abstract 3855: Circulating DNA methylation signatures enable early detection of gastrointestinal cancers.

Abstract Background: Early detection of gastrointestinal cancers remains a major clinical challenge due to their asymptomatic early stages—particularly for pancreatic and liver cancers—combined with the limited sensitivity of current screening modalities, inadequate identification of high-risk populations, and persistent disparities in surveillance access. Given the high mortality associated with pancreatic and liver cancers and the substantial global incidence of colorectal cancer, more effective early diagnostic strategies are urgently needed. Methods and Findings: We previously identified aberrant DNA methylation of ZFP30 and ZNF781 in circulating tumor DNA (ctDNA) from patients with pancreatic cancer, and aberrant methylation of TMEM240 in patients with colorectal cancer, with TMEM240 hypermethylation additionally associated with liver metastasis in gastrointestinal malignancies. In this study, we evaluated methylation levels of ZFP30/ZNF781 and TMEM240 in hepatocellular carcinoma (HCC) tumor tissues and matched adjacent normal tissues using qMSP, revealing significantly elevated methylation in all tumor samples. Aberrant methylation of these genes was also detected in plasma cell-free DNA (cfDNA) from patients with liver cancer. Analysis of TCGA Western cohorts further confirmed consistently increased methylation of these loci in pancreatic, colorectal, and liver cancers. Validation: We validated these biomarkers in independent Asian (Taiwan) and Western (U.S.) cohorts comprising 101 gastrointestinal cancer cases—including pancreatic, colon, rectal, and liver cancers—and 350 cancer-free healthy subjects. Aberrant methylation of ZFP30/ZNF781 and/or TMEM240 was detectable across all gastrointestinal cancer types analyzed. Results: Detection sensitivities were 93.8% for early-stage pancreatic cancer, 100% for late-stage pancreatic cancer, 90.62% for colon cancer, 99.0% for rectal cancer, and 90% for liver cancer, with a specificity of 98% in cancer-free controls. Conclusion: These results demonstrate that circulating DNA methylation signatures of ZFP30/ZNF781 and TMEM240provide a highly sensitive and specific non-invasive approach for detecting a broad spectrum of gastrointestinal cancers, supporting their potential utility as early detection biomarkers. Citation Format: Ruo-Kai Lin, YAO-YU HSIEH. Circulating DNA methylation signatures enable early detection of gastrointestinal cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3855.