Prognostic and predictive significance of long interspersed nucleotide element-1 methylation in advanced-stage colorectal cancer

Abstract

BackgroundHypomethylation of Long Interspersed Nucleotide Element-1 (LINE-1) is associated with worse prognosis in colorectal cancer (CRC). However, little is known about the relevance of this marker for the prognosis and response to chemotherapy of metastatic and recurrent (advanced-stage) CRC. Our aim was therefore to investigate whether tumor LINE-1 hypomethylation correlates with patient survival and with response to 5-fluorouracil (5-FU)/ oxaliplatin (FOLFOX) chemotherapy in advanced-stage CRC.MethodsThe study included 40 CRC patients who developed metastasis or local recurrence after surgery and subsequently underwent FOLFOX therapy. Progression-free and overall survival were estimated using the Kaplan-Meier method. LINE-1 methylation levels in formalin-fixed and paraffin-embedded primary tumor tissues were measured by MethyLight assay and correlated with patient survival. In vitro analyses were also conducted with human colon cancer cell lines having different LINE-1 methylation levels to examine the effects of 5-FU and oxaliplatin on LINE-1 activity and DNA double-strand-breaks.ResultsPatients with LINE-1 hypomethylation showed significantly worse progression-free (median: 6.6 vs 9.4 months; P = 0.02) and overall (median: 16.6 vs 23.2 months; P = 0.01) survival following chemotherapy compared to patients with high methylation. LINE-1 hypomethylation was an independent factor for poor prognosis (P = 0.018) and was associated with a trend for non-response to FOLFOX chemotherapy. In vitro analysis showed that oxaliplatin increased the LINE-1 score in LINE-1-expressing (hypomethylated) cancer cells, thereby enhancing and prolonging the effect of 5-FU against these cells. This finding supports the observed correlation between tumor LINE-1 methylation and response to chemotherapy in CRC patients.ConclusionsTumor LINE-1 hypomethylation is an independent marker of poor prognosis in advanced-stage CRC and may also predict non-response to combination FOLFOX chemotherapy. Prospective studies are needed to optimize the measurement of tumor LINE-1 methylation and to confirm its clinical impact, particularly as a predictive marker.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2984-8) contains supplementary material, which is available to authorized users.

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

“…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]. …”

Clinical Diagnostic Value for Colorectal Cancer Based on Serum CEA, CA24-2 and CA19-9

“…If peripheral blood miRNA is used as a tumor marker in clinic, reference range should be established and a standardized system should be established to ensure the accuracy and repeatability of miRNA detection. An increasing level of methylated DNA was association with advanced stage of colorectal cancer [50,51]. But the speci city of methylation detection is low.…”

Impact of Global DNA Methylation in Treatment Outcome of Colorectal Cancer Patients

“…Similarly, Barciszewska et al (2007) found lower 5mC level is correlated with advanced malignancy grade in breast and colon cancer. Improved patients‘ survival with global hypermethylation levels baseline ( Kaneko et al, 2016 ). In addition, LINE-1 hypermethylation is negatively associated with the T- stage and lymph node metastases in CRC patients ( Morikawa et al, 2012 ).…”