Impact of Tumor LINE-1 Methylation Level and Neoadjuvant Treatment and Its Association with Colorectal Cancer Survival

Abstract

Recent studies suggest that long-interspersed nucleotide element-1 (LINE-1) hypomethylation is commonly found in colorectal cancer (CRC), and is associated with worse prognosis. However, the utility of LINE-1 methylation on the prognosis of CRC is still controversial, and may be due to the fact that some clinical and pathological features may affect LINE-1 methylation. Thus, the aim of this study was to assess the prognostic value of tumor LINE-1 methylation in CRC, through their association with the CRC clinical and pathological characteristics. Survival of sixty-seven CRC patients was evaluated according to the median of tumor LINE-1 methylation, as well as pathological and oncological variables. We also studied the association between LINE-1 methylation and pathological features, and finally, we assessed the overall and disease-free survival of LINE1 methylation, stratified by neoadjuvant treatment and further checked by multivariate Cox regression to assess the statistical interactions. LINE-1 was hypomethylated in the CRC tumor with respect to the tumor adjacent-free area (p < 0.05), without association with any other clinical and oncological features, nor with overall and disease-free survival rates for CRC. Relevantly, in neoadjuvant treatment, LINE-1 methylation was associated with survival rates. Thus, disease-free and overall survival rates of treated CRC patients were worse in the hypomethylated LINE-1 tumors than those with normal LINE-1 methylation (p = 0.004 and 0.0049, respectively). Indeed, LINE-1 was hypermethylated more in the treated patients than in the non-treated patients (p < 0.05). The present study showed that tumor LINE-1 hypomethylation was associated with worse survival rates in only treated patients. Our data suggest an interactive effect of neoadjuvant treatment and tumor LINE-1 methylation, which could be a specific-tissue biomarker to predict survival of the treated patients, and help to personalize treatment in CRC.

Differential DNA methylation analysis of SUMF2, ADAMTS5, and PXDN provides novel insights into colorectal cancer prognosis prediction in Taiwan

“…LINE-1 is more hypomethylated in CRC tumors compared with adjacent normal tissue, and this is linked to metastasis. Moreover, LINE-1 is more hypermethylated in the neoplastic tissue of patients treated for CRC compared with untreated patients, and after neoadjuvant treatment, poor survival was observed in patients with tumor LINE-1 hypomethylation[ 26 ]. The results of a meta-analysis also support the idea that LINE-1 hypomethylation is considerably associated with the shortened OS and disease-free survival (DFS) of patients with CRC[ 27 ].…”

Value of methylation markers in colorectal cancer (Review)

“…Bachitta et al (82) conducted a meta-analysis in 2014, which described the role of LINE-1 hypomethylation in human cancer. It has also been shown that LINE-1 hypomethylation in CRC was associated with poor prognosis, survival and advanced stage, and that it could be a prognosis predictor of CRC (83,84). In addition to its prognosis value, a recent study reported that LINE-1 hypomethylation was effective in the early detection of CRC (85).…”

Epigenetic Alteration in Colorectal Cancer: Potential Diagnostic and Prognostic Implications

“…Previous research indicates that LINE-1 methylation in CRC adenomas is associated with polyp size and dysplasia severity. Therefore, low methylation and high expression of LINE-1 are conjectured to be associated with negative prognosis in CRC patients, with almost no heterogeneity in LINE-1 methylation within tumors [ 68 , 69 , 70 ]. Consequently, the combination of the fecal immunochemical test (FIT) with methylation biomarkers and low methylation of LINE-1 may enhance the sensitivity of screening and prognosis in CRC patients.…”