Eps15 Homology Domain-Containing Protein 3 Hypermethylation as a Prognostic and Predictive Marker for Colorectal Cancer

Abstract

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, Eps15 homology domain-containing protein 3 (EHD3) 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, EHD3 hypermethylation was detected in other gastrointestinal cancers. In the Asian CRC cohort, low EHD3 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, EHD3 hypermethylation was also connected to overall survival and lower chemotherapy and antimetabolite response rates. In conclusion, EHD3 hypermethylation contributes to the development of CRC in both Asian and Western populations.

Genomic and Transcriptomic Research in the Discovery and Application of Colorectal Cancer Circulating Markers

“…They validated EHD3, TMEM240, and SMAD3 on blood plasma samples from an independent group of CRC patients using the methods most accessible for clinics, namely, methyl-specific/methyl-sensitive PCR (Table 2). The results suggest that EHD3 is a potentially predictive marker as far as the response rate for chemotherapy was significantly higher in the patients displaying low circulating EHD3 methylation levels [77]. The hypermethylation in circulating TMEM240 was found to be valuable for the prognosis and early recurrence in colorectal cancer [70,70].…”

“…A recent work of the team led by Lin [70,70,77,84] gives an example of methylation CRC markers designed starting from the in-depth study. They conducted a bioinformatics analysis of data on the DNA methylation profile of a tumor and normal tissue available for research in the Cancer Genome Atlas.…”

“…COLVERA™ gives sufficient information about the surgical resection completeness, relapse-free survival and risk of residual disease [87]. Recently, this panel was expanded to three markers (BCAT1, IKZF1, and IRF4) detected by multiplexed real-time PCR and showed efficient detection on cfDNA [77]. The multi-panel test displayed a high sensitivity for CRC and HGD adenomas (71 and 23%, respectively) in the case of a positive result, which included those with ≥ 1 PCR replicates positive for either IKZF1 or IRF4, or at least two replicates positive for BCAT1, and a significantly improved specificity (94%) versus any PCR replicate positive.…”