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

Jiang, Di; Han, Xiaodong; Wen-ye, GU; Wang, Yu; Zheng, Qi; Zhang, Pin; Wu, Huimin; Zhu, Zhongzheng

doi:10.1631/jzus.b1000422

Cited by 21 publications

(24 citation statements)

References 45 publications

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“…Recent epigenetic evidence suggests that changes including reduced or increased methylation at LINE-1 DNA sequences in blood are associated with the risk of cervical precancer and a number of different cancers [11][12][13][14][15]. Thus, changes in LINE-1 methylation appear to be detectable even in normal tissue far from precancerous and/or tumor sites.…”

Section: Discussionmentioning

confidence: 99%

“…Long interspersed nucleotide element-1 (LINE-1) is a long terminal-repeat class of retroposons that is the most successfully integrated mobile element in the human genome and accounts for B20% of the human genome [9]. Generally, reduced LINE-1 methylation levels have been associated with cancer [10,11]. More recently, measures of LINE-1 methylation have been examined as potential phenotypic markers of cancer risk in peripheral blood or white blood cells.…”

Section: Introductionmentioning

confidence: 99%

“…More recently, measures of LINE-1 methylation have been examined as potential phenotypic markers of cancer risk in peripheral blood or white blood cells. After adjusting for known risk factors, epidemiologic studies have reported associations between LINE-1 methylation in blood and human papilloma virus-positive cervical precancer [12] and several different cancers including cancers of the liver, kidney, head and neck, and testicular germ cells [11,[13][14][15].…”

Section: Introductionmentioning

confidence: 99%

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LINE-1 methylation in peripheral blood and the risk of melanoma in melanoma-prone families with and without CDKN2A mutations

et al. 2013

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Cutaneous malignant melanoma (CMM) is an etiologically heterogenous disease with genetic, environmental (sun exposure), and host (pigmentation/nevi) factors and their interactions contributing to risk. Recently, epigenetic changes involving reduced levels of global DNA methylation in blood have been associated with genomic instability and cancer risk. We thus examined whether global methylation was associated with CMM risk in individuals from melanoma-prone families with and without CDKN2A germline mutations. We measured global DNA methylation using bisulfite pyrosequencing at four CpG sites of the long interspersed nucleotide element-1 (LINE-1) sequences in peripheral blood mononuclear cells (PBMCs) from individuals in 64 melanoma-prone families including 114 CMM cases (45 CDKN2A-positive and 69 CDKN2A-negative) and 121 unaffected individuals (31 CDKN2A-positive and 90 CDKN2A-negative). We used unconditional logistic regression to evaluate the association between CMM status and LINE-1 methylation levels, adjusting for age at blood draw and accounting for familial correlation in the variance. We found that male sex was significantly associated with higher overall LINE-1 methylation (P=0.0001). However, the overall and site-specific levels of LINE-1 methylation did not vary significantly by CMM status (overall odds ratio: 1.57, 95% confidence interval: 0.84-2.95, P=0.16; comparing lowest to highest or reference methylation group). Similar results were obtained when CDKN2A-positive and CDKN2A-negative families were analyzed separately. Our findings did not support a significant association between constitutional LINE-1 methylation in PBMCs and risk of CMM in melanoma-prone families with or without CDKN2A mutations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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LINE-1 methylation in peripheral blood and the risk of melanoma in melanoma-prone families with and without CDKN2A mutations

et al. 2013

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“…Furthermore, populations at different cancer risk are included, for instance, one report included elderly men at high cancer risk (79), whereas another included Asian women at lower risk of breast cancer (80). Some reports included more than 1 "study," because of use of different assays, different patient populations, or different study designs, so altogether there were 34 individual studies of genome-wide methylation (64,84,(87)(88)(89). Therefore, we report a revised meta-analysis including these studies (Fig.…”

Section: Comparison Of Published Reports Of Genomewide Methylation Inmentioning

confidence: 99%

“…A potential confounding factor in some retrospective studies is the possible effect of cancer treatment, as several commonly used neoadjuvant chemotherapeutic drugs are known affect inhibit activity of the folate-mediated 1-carbon metabolism pathway (93,94). Whereas this treatment-induced inhibition of DNA methylation could potentially explain the occurrence of genome-wide hypomethylation in posttreatment blood samples, 4 studies identifying significant associations between genomic hypomethylation and cancer prevalence, including 1 L1 study (87), and 3 5meC studies (31,72,73) used pretreatment sample only. Nonetheless, the exposure of cases, but not controls to cancer treatment may represent a confounding factor.…”

Section: Factors Affecting Epigenetic Epidemiologic Studiesmentioning

confidence: 99%

Is There a Link Between Genome-Wide Hypomethylation in Blood and Cancer Risk?

Brennan

Flanagan

2012

Cancer Prevention Research

103

104

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Cancer cells display widespread genetic and epigenetic abnormalities, but the contribution to disease risk, particularly in normal tissue before disease, is not yet established. Genome-wide hypomethylation occurs frequently in tumors and may facilitate chromosome instability, aberrant transcription and transposable elements reactivation. Several epidemiologic case-control studies have reported genomic hypomethylation in peripheral blood of cancer patients, suggesting a systemic effect of hypomethylation on disease predisposition, which may be exploited for biomarker development. However, more recent studies have failed to reproduce this. Here, we report a meta-analysis, indicating a consistent inverse association between genomic 5-methylcytosine levels and cancer risk [95% confidence interval (CI), 1.2-6.1], but no overall risk association for studies using surrogates for genomic methylation, including methylation at the LINE-1 repetitive element (95% CI, 0.8-1.7). However, studies have been highly heterogeneous in terms of experimental design, assay type, and analytical methods. We discuss the limitations of the current approaches, including the low interindividual variability of surrogate assays such as LINE1 and the importance of using prospective studies to investigate DNA methylation in disease risk. Insights into genomic location of hypomethylation, from recent whole genome, highresolution methylome maps, will help address this interesting and clinically important question. Cancer Prev Res; 5(12); 1345-57. Ó2012 AACR.

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Global methylation of blood leukocyte DNA and risk of melanoma

Shen

Song

Wan

et al. 2017

Intl Journal of Cancer

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Global DNA methylation, possibly influenced by lifestyle and environmental factors, has been suggested to play an active role in carcinogenesis. However, its role in melanoma has rarely been explored. The aims of this study were to evaluate the relationship between melanoma risk and expression of 5-methylcytosine (5-mC), a marker for global DNA methylation, in blood leukocyte DNA, and to determine whether this 5-mC level is influenced by pigmentation and sun exposure. This case-control study included 540 melanoma cases and 540 healthy controls. Overall, melanoma cases had significantly lower levels of 5-mC% than healthy controls (median: 3.24 vs 3.91, P<0.001). The significant difference between two groups did not differ by pigmentation or sun exposure. Among healthy controls, however, those who had fair skin color (P=0.041) or light or no tanning after prolonged sun exposure (P=0.031) or used a sunlamp (P=0.028) had lower levels of 5-mC% than their counterparts. In addition, those with an intermediate or high phenotypic index, an indicator of cutaneous cancer susceptibility, had 2.58-fold greater likelihood of having a low level of 5-mC% (odds ratio [OR]: 2.58; 95% confidence interval [CI]: 1.72, 3.96) than those with a low phenotypic index. Lower levels of 5-mC% were associated with a 1.25-fold greater risk of melanoma (OR: 1.25; 95% CI: 1.08, 1.37). A significant dose-response relationship was observed in quartile analysis (P=0.001). Our results suggest that global hypomethylation in blood leukocyte DNA is associated with increased risk of melanoma and that the level of methylation is influenced by pigmentation and sun exposure.

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

Cited by 21 publications

References 45 publications

LINE-1 methylation in peripheral blood and the risk of melanoma in melanoma-prone families with and without CDKN2A mutations

LINE-1 methylation in peripheral blood and the risk of melanoma in melanoma-prone families with and without CDKN2A mutations

Is There a Link Between Genome-Wide Hypomethylation in Blood and Cancer Risk?

Global methylation of blood leukocyte DNA and risk of melanoma

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