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.
Highlights
There is growing concern that colorectal cancer (CRC) will be the most frequent neoplasia of the 21th century [1]
Utilizing an overview of low and high long-interspersed nucleotide element-1 (LINE-1) methylation, we found for the first time a statistically significant association between tumor LINE-1 methylation and neoadjuvant treatment in CRC patients, which was related with survival outcomes
We evaluated approaches to provide new applications for the LINE-1 methylation in CRC prognosis
Summary
There is growing concern that colorectal cancer (CRC) will be the most frequent neoplasia of the 21th century [1]. The screening tests need to achieve high accuracy using new prognostic and predictive biomarkers in order to establish more personalized strategies in the prevention of CRC. In this context, epigenetic modifications, and in particular, DNA methylation, have been widely investigated in a variety of prognostic applications in cancer [3,4]. Cancer prevention through epigenetic biomarkers is of particular interest to the clinical practice, due to their specificity and the diagnostic capability. Methylation of specific tumor suppressor genes has emerged as a useful approach in clinical practice and been proposed by multiple studies as potential biomarkers [5,6,7]. Epigenetic biomarkers have been increasingly discussed in the literature, without standardized solutions or clinical validation yet, possibly due to the lack of adjusting for cofounding variables and pathological features that affect data reproducibility
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