Tumor LINE-1 Methylation Level in Association with Survival of Patients with Stage II Colon Cancer

Abstract

Genome-wide DNA hypomethylation is associated with a worse prognosis in early-stage colorectal cancer. To measure genome-wide DNA methylation levels, long interspersed nucleotide element (LINE-1) repeats are used as a surrogate marker. Cohort studies on the clinical impact of genome-wide DNA methylation level in patients with only early-stage colon cancer, are currently lacking. This study aimed to investigate the prognostic value of LINE-1 methylation in a stage II colon cancer cohort (n = 164). Manual needle microdissection of tumor areas was performed on formalin-fixed paraffin-embedded tumor tissue sections followed by DNA extraction. Bisulfite converted DNA was used to assess tumor LINE-1 methylation level by qPCR. Patients with LINE-1 hypomethylated tumors had a significantly worse overall survival compared to patients with a higher level of LINE-1 tumor DNA methylation (HR 1.68, 95% CI 1.03–2.75; p = 0.04). This effect was more prominent in patients aged over 65 years (HR 2.00, 95% CI 1.13–3.52; p = 0.02), although the test for age interaction was not significant. No significant effect on recurrence-free survival was observed. Based on these results, tumor LINE-1 hypomethylation is associated with a worse overall survival in stage II colon cancer. Whether the origin of this causation is cancer-specific or age-related can be debated.

Long Interspersed Element-1 Methylation Level as a Prognostic Biomarker in Gastrointestinal Cancers

“…They observed an approximately fivefold difference in cancer-specific mortality, as LINE-1 methylation in the tumor genes ranged from high to low [14]. Subsequent studies have confirmed the relationship between LINE-1 hypomethylation and poor prognosis in resected colorectal cancers [15-18]. In addition, LINE-1 hypomethylation has been reported to correlate with unfavorable outcomes in colon cancer patients receiving oxaliplatin with fluorouracil and folinic acid adjuvant chemotherapy [19-21].…”

Novel SFRP2 DNA Methylation Profile Following Neoadjuvant Therapy in Colorectal Cancer Patients with Different Grades of BMI

“…Genome-wide DNA hypo-methylation of LINE-1 is associated with a worse prognosis in early-stage colorectal cancer, though the majority of the performed studies did not reveal a relation between LINE-1 hypomethylation and clinical outcome in more advanced disease stages [40]. However, our study results confirmed this association, since we revealed a low methylation rate for LINE-1 in tumor samples, without any association or relationship with the clinical–pathological parameters of colorectal tumors.…”

Overview on Clinical Relevance of Intra-Tumor Heterogeneity

“…Hypomethylation of DNA in cancer cells can trigger cancer-germline genes with their activation ( 38 ) and the hypomethylation of intra-genomic endo-parasitic DNA repeats such as L1 with their reactivation and retrotransposition can increase genomic instability ( 39 , 40 ). L1 hypomethylation is present in NSCLC already in stage I tumors ( 41 ) and is related to worse survival in colon cancer stage II ( 42 ).…”