Abstract 4554: Advanced detection of <i>TMEM240</i> hypermethylation in circulating cell-free DNA as a novel biomarker for colorectal cancer monitoring

Abstract Background: Carcinoembryonic antigen (CEA) is currently the most widely utilized biomarker for monitoring colorectal cancer (CRC) progression and treatment efficacy. With a sensitivity of approximately 80% and specificity of 70% at a cutoff level of 5 μg/L, CEA has demonstrated clinical utility in many cases. However, 20-30% of CRC patients fail to benefit from CEA monitoring due to its limited dynamic range and clinical irrelevance in specific cases, underscoring the urgent need for more accurate and reliable biomarkers. Recent advancements have identified the hypermethylation of the TMEM240 gene as a promising biomarker for CRC detection, prognosis, and progression. Results: We developed an advanced detection technology to analyze methylated circulating cell-free DNA (mcfDNA) specific to the TMEM240 gene. A cohort of 30 colorectal cancer patients, including 5 with stage I and II, 3 with stage III, and 22 with stage IV, was monitored every 1-3 months over a follow-up period exceeding six months. The results revealed that elevated levels of TMEM240 mcfDNA could be detected 1-3 months before image progression. Notably, patients with good prognoses exhibited no detectable TMEM240 mcfDNA in their plasma, suggesting and good predictive marker of treatment response. In contrast, metastatic colorectal cancer patients with detectable TMEM240 mcfDNA in plasma were identified as having a higher risk of cancer progression. Furthermore, high levels of TMEM240 mcfDNA were strongly associated with the development of multiple metastases within three months, emphasizing its prognostic value in advanced disease stages. The method exhibited outstanding accuracy in predicting cancer progression, achieving an area under the curve (AUC) of 0.986, a sensitivity of 92.3%, and a specificity exceeding 99.0%. These results highlight the superiority of TMEM240 mcfDNA as a biomarker compared to CEA, particularly in its ability to provide earlier and more precise detection of disease progression. Unlike CEA, which often fails to reflect subtle or early changes in CRC dynamics, TMEM240 mcfDNA levels demonstrated robust applicability across all stages of CRC, from early detection in stages I and II to advanced monitoring in stage IV cases. TMEM240 mcfDNA levels also provided real-time insights into treatment efficacy, particularly in metastatic colorectal cancer patients. Conclusion: The hypermethylation of TMEM240 mcfDNA in plasma represents a highly sensitive and specific biomarker for CRC monitoring, addressing the limitations of traditional markers such as CEA. The integration of this innovative assay into clinical practice could revolutionize CRC management by enabling earlier detection of progression, more accurate prognosis, and real-time evaluation of therapeutic efficacy. Citation Format: Yao-Yu Hsieh, Ruo-Kai Lin. Advanced detection of TMEM240 hypermethylation in circulating cell-free DNA as a novel biomarker for colorectal cancer monitoring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4554.