Inter-locus as well as intra-locus heterogeneity in LINE-1 promoter methylation in common human cancers suggests selective demethylation pressure at specific CpGs

Nüsgen, Nicole; Goering, Wolfgang; Daukša, Albertas; Biswas, Arijit; Jamil, Muhammad Ahmer; Dimitriou, Ioanna M.; Sharma, Amit; Singer, Heike; Fimmers, Rolf; Fröhlich, Holger; Oldenburg, Johannes; Gulbinas, Antanas; Schulz, Wolfgang A.; El‐Maarri, Osman

doi:10.1186/s13148-015-0051-y

Cited by 33 publications

(44 citation statements)

References 42 publications

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“…() (c), and Nüsgen et al. () (d); the bracket labeled “a” indicates the CpG‐sites covered by the PyroMark LINE ‐1 kit (Qiagen, Hilden, Germany). (A) Summary of significant differences between tumor and healthy neighboring tissue (*,**, and *** correspond to significant values of p < 0.05, <0.005, and <0.0005); n: nonsignificant; based on data in Figure ).…”

Section: Resultsmentioning

confidence: 99%

“…For instance, in a comparison of multiple cancer types, Nüsgen et al. () observed that tumors could be ranked by their LINE‐1 hypomethylation levels with urinary bladder cancers being most hypomethylated followed by prostate, colon, and stomach cancers. The mechanism underlying the preferential hypomethylation in certain cancer types are still obscure.…”

Section: Introductionmentioning

confidence: 99%

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Detailed methylation map of LINE‐1 5′‐promoter region reveals hypomethylated CpG hotspots associated with tumor tissue specificity

Sharma¹,

Jamil²,

Nuesgen³

et al. 2019

Molec Gen & Gen Med

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Background Long interspersed nuclear elements ( LINE ‐1) sequences constitute a substantial portion of the human genome, and their methylation often correlating with global genomic methylation. Previous studies have highlighted the feasibility of using LINE ‐1 methylation to discriminate tumors from healthy tissues. However, most studies are based on only a few specific LINE ‐1 CpG sites. Methods Herein, we have performed a systematic fine‐scale analysis of methylation at 14 CpGs located in the 5′‐region of consensus LINE ‐1, in bladder, colon, prostate, and gastric tumor tissues using a global degenerate approach. Results Our results reveal variable methylation levels between different CpGs, as well as some tissue‐specific differences. Trends toward hypomethylation were observed in all tumors types to certain degrees, showing statistically significance in bladder and prostate tumors. Our data points toward the presence of unique LINE ‐1 DNA methylation patterns for each tumor type and tissue, indicating that not the same CpGs will be informative for testing in all tumor types. Conclusion This study provides an accurate guide that will help to design further assays that could avoid artifacts and explain the variability of obtained LINE ‐1 methylation values between different studies.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Detailed methylation map of LINE‐1 5′‐promoter region reveals hypomethylated CpG hotspots associated with tumor tissue specificity

Sharma¹,

Jamil²,

Nuesgen³

et al. 2019

Molec Gen & Gen Med

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“…DNA methylation profiles within specific genes can affect their transcriptional patterns and can be altered by exogenous stressors. Given that DNA hypermethylation-induced silencing of tumor-suppressor genes and hypomethylation-induced activation of oncogenes have been described in virtually all human cancers and are considered driving mechanisms of carcinogenesis (Portela & Esteller, 2010; Heyn & Esteller, 2012; Jones, 2012; Johnson et al, 2015; Nüsgen et al, 2015), the potential for IR-induced changes in gene-specific DNA methylation that affect changes in expression are critically important.…”

Section: Ionizing Radiation and Gene-specific Dna Methylationmentioning

confidence: 99%

Effects of ionizing radiation on DNA methylation: from experimental biology to clinical applications

Miousse

Kutanzi

Koturbash

2017

International Journal of Radiation Biology

134

100

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Purpose Ionizing radiation (IR) is a ubiquitous environmental stressor with genotoxic and epigenotoxic capabilities. Terrestrial IR, predominantly a low-linear energy transfer (LET) radiation, is being widely utilized in medicine, as well as in multiple industrial applications. Additionally, an interest in understanding the effects of high-LET irradiation is emerging due to the potential of exposure during space missions and the growing utilization of LET radiation in medicine. Conclusions In this review, we summarize the current knowledge of the effects of IR on DNA methylation, a key epigenetic mechanism regulating the expression of genetic information. We discuss global, repetitive elements and gene-specific DNA methylation in light of exposure to high and low doses of high- or low-LET IR, fractionated IR exposure, and bystander effects. Finally, we describe the mechanisms of IR-induced alterations to DNA methylation and discuss ways in which that understanding can be applied clinically, including utilization of DNA methylation as a predictor of response to radiotherapy and in the manipulation of DNA methylation patterns for tumor radiosensitization.

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“…Barry et al 32 reported Alu hypermethylation in blood of patients with prostate cancer. Additionally, both hypomethylation and hypermethylation of LINE-1 CpGs were detected in the blood of patients with pancreatic, colon, and gastric cancer 33. Taken together, these recent reports demonstrate that the pattern of LINE-1 methylation in blood is quite variable, in a clear contrast to tumor samples, which in general exhibit a genome-wide hypomethylation.…”

Section: Discussionmentioning

confidence: 68%

Line-1 Hypomethylation and Mutational Status in Cutaneous Melanomas

Pramio

Pennacchi

Maria‐Engler

et al. 2016

Journal of Investigative Medicine

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Epigenetic dysregulation is an important emerging hallmark of cutaneous melanoma development. The global loss of DNA methylation in gene-poor regions and transposable DNA elements of cancer cells contributes to increased genomic instability. Long interspersed element-1 (LINE-1) sequences are the most abundant repetitive sequence of the genome and can be evaluated as a surrogate marker of the global level of DNA methylation. In this work, LINE-1 methylation levels were evaluated in cutaneous melanomas and normal melanocyte primary cell cultures to investigate their possible association with both distinct clinicopathological characteristics and tumor mutational profile. A set of driver mutations frequently identified in cutaneous melanoma was assessed by sequencing (actionable mutations in BRAF, NRAS, and KIT genes, and mutations affecting the TER T promoter) or multiplex ligation-dependent probe amplification (MLPA) (CDKN2A deletions). Pyrosequencing was performed to investigate the methylation level of LINE-1 and CDKN2A promoter sequences. The qualitative analysis showed a trend toward an association between LINE-1 hypomethylation and CDKN2A inactivation (p=0.05). In a quantitative approach, primary tumors, mainly the thicker ones (>4 mm), exhibited a trend toward LINE-1 hypomethylation when compared with control melanocytes. To date, this is the first study reporting in cutaneous melanomas a possible link between the dysregulation of LINE-1 methylation and the presence of driver mutations.

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Inter-locus as well as intra-locus heterogeneity in LINE-1 promoter methylation in common human cancers suggests selective demethylation pressure at specific CpGs

Cited by 33 publications

References 42 publications

Detailed methylation map of LINE‐1 5′‐promoter region reveals hypomethylated CpG hotspots associated with tumor tissue specificity

Detailed methylation map of LINE‐1 5′‐promoter region reveals hypomethylated CpG hotspots associated with tumor tissue specificity

Effects of ionizing radiation on DNA methylation: from experimental biology to clinical applications

Line-1 Hypomethylation and Mutational Status in Cutaneous Melanomas

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