Serum LINE-1 hypomethylation as a potential prognostic marker for hepatocellular carcinoma

Tangkijvanich, Pisit; Hourpai, Nusara; Rattanatanyong, Prakasit; Wisedopas, Naruemon; Mahachai, Varocha; Mutirangura, Apiwat

doi:10.1016/j.cca.2006.12.029

Cited by 121 publications

(98 citation statements)

References 27 publications

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“…Firstly, this was a hospital-based case-control study, which may result in selection bias of participants. Moreover, given that DNA methylation in cancer patients was measured after cancer diagnosis and DNA hypomethylation could be detected in sera as well as HCC cells in peripheral blood of HCC cases (Tangkijvanich et al, 2007;Lee et al, 2009), blood DNA hypomethylation in cancer patients we observed may partly represent the methylation level of DNA derived from HCC cells. As degree of hypomethylation in tumor cells and number of HCC cells in circulating peripheral blood progress according to increased tumor stage, further analyses of LINE-1 methylation in relation to HCC risk were repeated using cases only with early stage of tumor (Stage I/II), which showed no major differences in risk estimates from the results based on the total number of cases (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Association of hypomethylation of LINE-1 repetitive element in blood leukocyte DNA with an increased risk of hepatocellular carcinoma

Jiang

Han

Wen-ye

et al. 2011

J. Zhejiang Univ. Sci. B

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Abstract:Global DNA hypomethylation has been associated with increased risk for cancers of the colorectum, bladder, breast, head and neck, and testicular germ cells. The aim of this study was to examine whether global hypomethylation in blood leukocyte DNA is associated with the risk of hepatocellular carcinoma (HCC). A total of 315 HCC cases and 356 age-, sex-and HBsAg status-matched controls were included. Global methylation in blood leukocyte DNA was estimated by analyzing long interspersed element-1 (LINE-1) repeats using bisulfite-polymerase chain reaction (PCR) and pyrosequencing. We observed that the median methylation level in HCC cases (percentage of 5-methylcytosine (5mC)=77.7%) was significantly lower than that in controls (79.5% 5mC) (P=0.004, Wilcoxon rank-sum test). The odds ratios (ORs) of HCC for individuals in the third, second, and first (lowest) quartiles of LINE-1 methylation were 1.1 (95% confidence interval (CI) 0.7-1.8), 1.4 (95% CI 0.8-2.2), and 2.6 (95% CI 1.7-4.1) (P for trend <0.001), respectively, compared to individuals in the fourth (highest) quartile. A 1.9-fold (95% CI 1.4-2.6) increased risk of HCC was observed among individuals with LINE-1 methylation below the median compared to individuals with higher (>median) LINE-1 methylation. Our results demonstrate for the first time that individuals with global hypomethylation measured in LINE-1 repeats in blood leukocyte DNA have an increased risk for HCC. Our data provide the evidence that global hypomethylation detected in the easily obtainable DNA source of blood leukocytes may help identify individuals at risk of HCC.

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Section: Discussionmentioning

confidence: 99%

Association of hypomethylation of LINE-1 repetitive element in blood leukocyte DNA with an increased risk of hepatocellular carcinoma

Jiang

Han

Wen-ye

et al. 2011

J. Zhejiang Univ. Sci. B

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“…Besides being a surrogate marker, LINE-1 and ALU methylations have also attracted attention as molecular markers for tumor detection as well as the prediction of tumor treatment response and prognosis. 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.…”

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confidence: 99%

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

Bae

Shin

Kwon

et al. 2012

Intl Journal of Cancer

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Focal CpG island hypermethylation and diffuse genomic hypomethylation signify the changes in the DNA methylation status in cancer cells. ALU and LINE-1 repetitive DNA elements comprise~28% of the human genome. PCR-based measurements of these repetitive DNA elements can be used as a surrogate marker of the genomewide methylation content. Our study aimed to identify the timing of ALU and LINE-1 hypomethylations during multistep gastric carcinogenesis and their prognostic implications in gastric cancer (GC). In our study, we analyzed the methylation statuses of ALU and LINE-1 in 249 cases of gastric biopsy samples and another independent set of 198 cases of advanced GC by pyrosequencing. Regardless of the Helicobacter pylori infection status, a significant decrease in the ALU methylation levels was noted during the transitions from chronic gastritis to intestinal metaplasia and from gastric adenoma to GC. LINE-1 methylation decreased during the transition from intestinal metaplasia to gastric adenoma and no further decrease occurred during the transition from gastric adenoma to GC. A low LINE-1 methylation status was strongly associated with poor prognosis in GC. A multivariate analysis revealed that LINE-1 methylation status was an independent prognostic factor. Our findings suggest that ALU and LINE-1 hypomethylations are early events during multistep gastric carcinogenesis. Furthermore, the LINE-1 methylation status can be used as a molecular biomarker to define a subset of GC patients with poor prognosis.Focal promoter CpG island hypermethylation and generalized genomic hypomethylation signify the changes in the DNA methylation status in human cancer cells. Promoter CpG island hypermethylation is an important mechanism that inactivates tumor suppressor and tumor-related genes; meanwhile, generalized genomic hypomethylation contributes to genomic or chromosomal instability.1-3 Genomic hypomethylation mainly affects repetitive transposable DNA elements, which comprise 45% of the human genome 4 ; these elements reside mainly in the intergenic and intronic regions of the genome and in noncoding and coding exons of the genome to a much lesser extent.5 Long interspersed nucleotide element-1 (LINE-1) and ALU are major constituents of interspersed DNA repeats, constituting $17% and 11% of the human genome, respectively. 4CpG sites located within LINE-1 and ALU are usually methylated in normal somatic tissues, a mechanism that is believed to have evolved as a major defense mechanism to repress these transposable genetic elements.6 Demethylation of transposable elements is hypothesized to facilitate genomic instability by leading to retrotransposition of transposable elements, hypomethylated genome-associated error-prone repair of replication-independent endogenous double-strand breaks, and dysregulation of DNA repair genes. [7][8][9][10][11] In addition to bringing about genomic structural variation, demethylation of transposable element promoters dysregulates gene expression by upregulating the transcription of genes l...

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“…LINE-1, or L1, is the most abundant and well-known LINE (14,29). The methylation status of Alu, LINE-1, and HERV-K, a well-known member of HERV, has been reported for many cancers (5,8,16,19,50,51,55,60). Recently, Bollati et al (6) reported an age-related methylation of peripheral blood mononuclear cells (PBMC) of Alu and LINE-1.…”

mentioning

confidence: 99%

“…Age-dependent global hypomethylation has been shown to be associated with many diseases (20,27,49,55). Moreover, in cancer, global hypomethylation is associated with more advanced stages and poor prognosis (30,31,36,39,40,43,50,51). Therefore, it is important to understand how the same epigenetic characteristic is associated with a variety of cellular phenotypes.…”

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confidence: 99%

Distinctive patterns of age-dependent hypomethylation in interspersed repetitive sequences

Jintaridth

Mutirangura

2010

Physiological Genomics

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Serum LINE-1 hypomethylation as a potential prognostic marker for hepatocellular carcinoma

Cited by 121 publications

References 27 publications

Association of hypomethylation of LINE-1 repetitive element in blood leukocyte DNA with an increased risk of hepatocellular carcinoma

Association of hypomethylation of LINE-1 repetitive element in blood leukocyte DNA with an increased risk of hepatocellular carcinoma

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

Distinctive patterns of age-dependent hypomethylation in interspersed repetitive sequences

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