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.
Highlights
Hypomethylation of Long Interspersed Nucleotide Element-1 (LINE-1) is associated with worse prognosis in colorectal cancer (CRC)
An receiver operating characteristic (ROC) curve was constructed to assess response or no response to FOLFOX chemotherapy according to tumor LINE-1 methylation (Fig. 3a)
Multivariate analysis by COX proportional hazard model demonstrated that LINE-1 hypomethylation was an independent factor for poor prognosis (P = 0.018; Table 2, Additional file 5: Table S3, Additional file 6: Figure S3)
Summary
Hypomethylation of Long Interspersed Nucleotide Element-1 (LINE-1) is associated with worse prognosis in colorectal cancer (CRC). 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 to investigate whether tumor LINE-1 hypomethylation correlates with patient survival and with response to 5fluorouracil (5-FU)/ oxaliplatin (FOLFOX) chemotherapy in advanced-stage CRC. The incidence of CRC is increasing, mortality from CRC has decreased in many countries [1] This trend is likely due to early diagnosis and the development of multidisciplinary treatments [2]. Emerging evidence indicates that epigenetic mechanisms such as aberrant DNA methylation can trigger resistance to 5-FU, oxaliplatin and irinotecan in CRC [9]. Tumor DNA hypermethylation has been implicated in chemoresistance [13, 14], little is known about its relationship to oxaliplatin resistance
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