Hypermethylation and decreased expression of TMEM240 are potential early-onset biomarkers for colorectal cancer detection, poor prognosis, and early recurrence prediction

Abstract

Background: Gene silencing by aberrant DNA methylation of promoter regions remains the most dominant phenomenon occurring during tumorigenesis. Improving the early diagnosis, prognosis, and recurrence prediction of colorectal cancer using noninvasive aberrant DNA methylation biomarkers has encouraging potential. The aim of this study is to characterize the DNA methylation of the promoter region of TMEM240, as well as gene expression and its effect on cell biological functions and its applications in early detection and outcome prediction. Results: Highly methylated CpG sites were identified in the TMEM240 gene by Illumina methylation 450K arrays in 26 Taiwanese patient paired samples and 38 paired samples from The Cancer Genome Atlas (TCGA) colorectal cancer dataset. Transient transfection and knockdown of TMEM240 were performed to demonstrate the role of TMEM240 in colorectal cancer cells. The data showed that TMEM240 could lead to G1 cell cycle arrest, repress cancer cell proliferation, and inhibit cancer cell migration. The quantitative methylation-specific real-time polymerase chain reaction (PCR) results revealed that 87.8% (480 of 547) of the colorectal cancer tumors had hypermethylated TMEM240, and this was also found in benign tubular adenomas (55.6%). Circulating cell-free methylated TMEM240 was detected in 13 of 25 (52.0%) Taiwanese colorectal cancer patients but in fewer (28.6%) healthy controls. In 72.0% (85/118) of tissue samples, TMEM240 mRNA expression was lower in Taiwanese CRC tumor tissues than in normal colorectal tissues according to real-time reverse transcription PCR results, and this was also found in benign tubular adenomas (44.4%). The TMEM240 protein was analyzed in South Korean and Chinese CRC patient samples using immunohistochemistry. The results exhibited low protein expression in 91.7% (100/109) of tumors and 75.0% (24/32) of metastatic tumors but exhibited high expression in 75.0% (6/8) of normal colon tissues. Multivariate Cox proportional hazards regression

Promising Epigenetic Biomarkers for the Early Detection of Colorectal Cancer: A Systematic Review

“…Low expression of the TMEM240 protein has been observed in about half of patients with inflammatory bowel diseases, which have a three to five times higher risk of developing colorectal cancer. The study’s results showed that hypermethylation and low expression of TMEM240 are potential biomarkers for colorectal cancer detection, poor prognosis, and early recurrence prediction [ 95 ].…”

The role of multiple metabolic genes in predicting the overall survival of colorectal cancer: A study based on TCGA and GEO databases

“…Earlier, the clinical prediction of prognosis was primarily based on clinicopathological characteristics such as age, pathological grade, and TNM staging. As these clinicopathological characteristics are highly biased, it is difficult to make a precise prediction of the prognosis based on them [ 26 , 27 ]. In recent years, research studies based on the mRNA characteristic (such as alpha-fetoprotein in liver cancer and prostate-specific antigen in prostate cancer, and so on) for predicting the mortality risk of cancer has become a new hotspot for researchers, but so far, none of these studies were able to identify reliable indicators for the prediction of CRC prognosis [ 28 ].…”

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

“…Naturally, the correlation between EHD3 promoter hypermethylation and reduced EHD3 transcript level was significant in both cohorts ( Figure 3 B and Figure 4 A). Because EHD3 promoter hypermethylation was found in 72.6% of Taiwanese CRC tissues, which was higher than SEPT9 hypermethylation found in 60.92% of Taiwanese CRC tissues [ 28 ] and in 44.4% of patients with tubular polyp adenomas, EHD3 hypermethylation can serve as an early indicator of CRC or as a viable auxiliary to the pathological diagnosis of malignant polyps.…”