| Summary: | Colorectal cancer (CRC) arises from chromosomal instability, resulting from aberrant hypermethylation in tumor suppressor genes. This study identified hypermethylated genes in CRC and investigated how they affect clinical outcomes. Methylation levels of specific genes were analyzed from The Cancer Genome Atlas dataset and 20 breast cancer, 16 esophageal cancer, 33 lung cancer, 15 uterine cancer, 504 CRC, and 9 colon polyp tissues and 102 CRC plasma samples from a Taiwanese cohort. In the Asian cohort, <i>Eps15 homology domain-containing protein 3</i> (<i>EHD3</i>) had twofold higher methylation in 44.4% of patients with colonic polyps, 37.3% of plasma from CRC patients, and 72.6% of CRC tissues, which was connected to vascular invasion and high microsatellite instability. Furthermore, <i>EHD3</i> hypermethylation was detected in other gastrointestinal cancers. In the Asian CRC cohort, low <i>EHD3</i> mRNA expression was found in 45.1% of patients and was connected to lymph node metastasis. Multivariate Cox proportional-hazards survival analysis revealed that hypermethylation in women and low mRNA expression were associated with overall survival. In the Western CRC cohort, <i>EHD3</i> hypermethylation was also connected to overall survival and lower chemotherapy and antimetabolite response rates. In conclusion, <i>EHD3</i> hypermethylation contributes to the development of CRC in both Asian and Western populations.
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