Long interspersed nuclear element‐1 hypomethylation is a potential biomarker for the prediction of response to oral fluoropyrimidines in microsatellite stable and CpG island methylator phenotype‐negative colorectal cancer

Abstract

We investigated the clinical value of methylation of long interspersed nuclear element-1 (LINE-1) for the prognosis of colorectal cancer (CRC) and for the survival benefit from adjuvant chemotherapy with oral fluoropyrimidines. LINE-1 methylation in tumor DNA was measured by quantitative methylation-specific PCR in 155 samples of stage II and stage III CRC. The presence of microsatellite instability and CpG island methylator phenotype (CIMP) were assessed and 131 microsatellite stable ⁄ CIMP) cases were selected for survival analysis, of which 77 patients had received postoperative adjuvant chemotherapy with oral fluoropyrimidines. The CRC cell lines were used to investigate possible mechanistic links between LINE-1 methylation and effects of 5-fluorouracil (5-FU). High LINE-1 methylation was a marker for better prognosis in patients treated by surgery alone. Patients with low LINE-1 methylation who were treated with adjuvant chemotherapy survived longer than those treated by surgery alone, suggestive of a survival benefit from the use of oral fluoropyrimidines. In contrast, a survival benefit from chemotherapy was not observed for patients with high LINE-1 methylation. The CRC cell lines treated with 5-FU showed increased expression of LINE-1 mRNA. This was associated with upregulation of the phospho-histone H2A.X in cells with low LINE-1 methylation, but not in cells with high LINE-1 methylation. The 5-FU-mediated induction of phospho-histone H2A.X, a marker of DNA damage, was inhibited by knockdown of LINE-1. These results suggest that LINE-1 methylation is a novel predictive marker for survival benefit from adjuvant chemotherapy with oral fluoropyrimidines in CRC patients. This finding could be important for achieving personalized chemotherapy. (Cancer Sci 2011; 102: 166-174) E pigenetic alterations including CpG island hypermethylation and global hypomethylation of DNA are commonly observed in colorectal cancer (CRC).(1) The aberrant hypermethylation of CpG islands is associated with distinctive clinical features of CRC and shows promise as a diagnostic marker. (2,3) Global hypomethylation, on the other hand, has attracted much less attention and its clinical significance in cancer has not been extensively investigated.Long interspersed nuclear element-1 (LINE-1) is a non-longterminal-repeat class of retroposon that is the most successfully integrated mobile element and accounts for approximately 18% of the human genome.(4-6) The LINE-1 sequence is 6 kb in length and contains a 5¢ untranslated region (UTR), two open reading frames and a 3¢UTR. The 5¢UTR has internal promoter activity and the open reading frame encodes for nuclease and reverse transcriptase activities that are necessary for transposition. Although the majority of retroposons no longer have the ability to transpose due to mutations and deletions in their sequence, approximately 100 full-length copies of LINE-1 in the human genome retain this ability. (7,8) Because of the abundance and functional ability of LINE-1, the level of its methyla...

Different Involvement of DNA Methylation and Histone Deacetylation in the Expression of Solute-Carrier Transporters in 4 Colon Cancer Cell Lines

“…As mentioned above, both HCT116 and SW48 cell lines represent CIMP phenotype. 28) According to the report by Mossman et al, 29) HCT116 and SW48 cell lines are known to harbor epigenetic changes, and were among the most affected by DAC, which may suggest that regulation of DNA methylation in these cell lines is different from that in others. In addition, HCT116 and SW48 cells have been used for the analysis of DNA methylation.…”

ALU and LINE‐1 hypomethylations in multistep gastric carcinogenesis and their prognostic implications

“…26 LINE-1 methylation has been investigated as a screening tool for cancer detection in blood 27,28 and oral rinse samples 29 as well as a surrogate marker for predicting treatment response to chemotherapy. 30,31 Several studies have demonstrated an association between LINE-1 or ALU hypomethylation and poor clinical outcomes in cancer or clinicopathological parameters indicative of poor prognosis. 12,[32][33][34][35] However, little information is currently available about the prognostic value of repetitive DNA elements in GC.…”

Pretreatment Serum Cea as a Predictive Biomarker for the Response to Neoadjuvant Chemoradiotherapy: A Meta-Analysis in Rectal Cancer

“…For this reason, other biomarkers and genetic predictors, such as p21, p53, Bax, Bcl2, COX2, VEGF, EGFR and thymidylate synthase [41][42][43], have been studied. Some newly predictive biomarkers are also reported, including Cathepsin S [44], expression of CD133 [45], methylation of long interspersed nuclear element-1(LINE-1) [46], and GRP78 the 78-kDa glucose-regulated protein [47], but some of them are contradictory. These new biomarkers may help predict which patients may respond, but they could not directly translate into widely and low-cost clinical use.…”