Long Interspersed Nucleotide Element 1 Hypomethylation Is Associated With Poor Prognosis of Lung Adenocarcinoma

Ikeda, Koei; Shiraishi, Kenji; Eguchi, Ayami; Shibata, Hidekatsu; Yoshimoto, Kentaro; Mori, Takeshi; Baba, Yoshifumi; Baba, Hideo; Suzuki, Makoto

doi:10.1016/j.athoracsur.2013.06.035

Cited by 36 publications

(26 citation statements)

References 35 publications

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“…LINE-1 hypomethylation has been demonstrated as a poor prognostic maker in various human cancers such as colorectal [34], gastric [18], esophageal [35], and lung cancer [24], [36]. Alu hypomethylation has also been studied in human cancers, but its prognostic value is unclear in contrast to LINE-1 .…”

Section: Discussionmentioning

confidence: 99%

Alu and LINE-1 Hypomethylation Is Associated with HER2 Enriched Subtype of Breast Cancer

et al. 2014

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The changes in DNA methylation status in cancer cells are characterized by hypermethylation of promoter CpG islands and diffuse genomic hypomethylation. Alu and long interspersed nucleotide element-1 (LINE-1) are non-coding genomic repetitive sequences and methylation of these elements can be used as a surrogate marker for genome-wide methylation status. This study was designed to evaluate the changes of Alu and LINE-1 hypomethylation during breast cancer progression from normal to pre-invasive lesions and invasive breast cancer (IBC), and their relationship with characteristics of IBC. We analyzed the methylation status of Alu and LINE-1 in 145 cases of breast samples including normal breast tissue, atypical ductal hyperplasia/flat epithelial atypia (ADH/FEA), ductal carcinoma in situ (DCIS) and IBC, and another set of 129 cases of IBC by pyrosequencing. Alu methylation showed no significant changes during multistep progression of breast cancer, although it tended to decrease during the transition from DCIS to IBC. In contrast, LINE-1 methylation significantly decreased from normal to ADH/FEA, while it was similar in ADH/FEA, DCIS and IBC. In IBC, Alu hypomethylation correlated with negative estrogen receptor (ER) status, and LINE-1 hypomethylation was associated with negative ER status, ERBB2 (HER2) amplification and p53 overexpression. Alu and LINE-1 methylation status was significantly different between breast cancer subtypes, and the HER2 enriched subtype had lowest methylation levels. In survival analyses, low Alu methylation status tended to be associated with poor disease-free survival of the patients. Our findings suggest that LINE-1 hypomethylation is an early event and Alu hypomethylation is probably a late event during breast cancer progression, and prominent hypomethylation of Alu and LINE-1 in HER2 enriched subtype may be related to chromosomal instability of this specific subtype.

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Section: Discussionmentioning

confidence: 99%

Alu and LINE-1 Hypomethylation Is Associated with HER2 Enriched Subtype of Breast Cancer

et al. 2014

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“…The role of epigenetic alterations, including aberrant methylation and expression of LINE-1 elements in the development and promotion of radiation-induced fibrosis and lung cancer is becoming increasingly recognized (Ikeda et al, 2013; Saito et al, 2010; Weigel et al, 2015). In our previous studies, we reported the long-term dose-dependent genomic and LINE-1 ORF1-associated DNA hypermethylation in the mouse lung 5 months after exposure to heavy iron ions ( 56 Fe) (Nzabarushimana et al, 2014), but failed to identify changes in LINE-1 ORF1 methylation four weeks after exposure to either protons or 56 Fe exposure, or as a result of the sequential exposure to both (Nzabarushimana et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Densely ionizing radiation affects DNA methylation of selective LINE-1 elements

Prior

Miousse

Nzabarushimana

et al. 2016

Environmental Research

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Long Interspersed Nucleotide Element 1 (LINE-1) retrotransposons are heavily methylated and are the most abundant transposable elements in mammalian genomes. Here, we investigated the differential DNA methylation within the LINE-1 under normal conditions and in response to environmentally relevant doses of sparsely and densely ionizing radiation. We demonstrate that DNA methylation of LINE-1 elements in the lungs of C57BL6 mice is dependent on their evolutionary age, where the elder age of the element is associated with the lower extent of DNA methylation. Exposure to 5-aza-2′-deoxycytidine and methionine-deficient diet affected DNA methylation of selective LINE-1 elements in an age- and promoter type-dependent manner. Exposure to densely IR, but not sparsely IR, resulted in DNA hypermethylation of older LINE-1 elements, while the DNA methylation of evolutionary younger elements remained mostly unchanged. We also demonstrate that exposure to densely IR increased mRNA and protein levels of LINE-1 via the loss of the histone H3K9 dimethylation and an increase in the H3K4 trimethylation at the LINE-1 5′-untranslated region, independently of DNA methylation. Our findings suggest that DNA methylation is important for regulation of LINE-1 expression under normal conditions, but histone modifications may dictate the transcriptional activity of LINE-1 in response to exposure to densely IR.

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“…The L1 methylation level has been shown to decrease in gastric epithelial cells with the progression of the lesion along the multistep gastric carcinogenesis, although there are wide variations in L1 methylation levels in gastric cancers (GCs) [7,8]. Low L1 methylation status has been demonstrated to be closely associated with shorter survival of the cancer patient, not only for GCs [7,8] but also for colon cancers [9], rectal cancers [10], esophageal squamous cell carcinomas [11], and lung adenocarcinomas [12,13].…”

Section: Introductionmentioning

confidence: 99%

Methylation status of long interspersed element-1 in advanced gastric cancer and its prognostic implication

et al. 2015

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Backgrounds Reportedly, the pyrosequencing methylation assay can produce inconsistent results between paired snap-frozen and formalin-fixed paraffin-embedded archival tissue samples. In this study, we assayed the methylation levels at four individual CpG sites of L1 using pyrosequencing and found that the methylation levels at individual CpG sites were different but were closely correlated between paired snap-frozen and formalin-fixed paraffinembedded tissue samples. We aimed to determine whether low methylation status of L1 is associated with gastric cancer patient prognosis. Methods We analyzed 434 formalin-fixed paraffinembedded tissue samples of advanced gastric cancer for their methylation status at four CpG sites of L1 [nucleotide positions 328, 321, 318, and 306 of X58075 (Genbank)] using pyrosequencing, and correlated the L1 methylation level with clinicopathological features.Results Older age at onset, males, tumor location at antrum or lower body, intestinal type, and lymphatic or venous invasion were associated with a low average methylation level of L1 at the two CpG sites 1 and 4 combined. The average methylation level of L1 at CpG sites 1 and 4 combined was significantly lower in microsatellite-stable and EBV-negative gastric cancers than in EBV-positive or microsatellite-unstable gastric cancers. Low methylation status of L1 was independently correlated with shorter overall survival and disease-free survival time. Conclusion Our findings indicate that the discrepancy in the methylation level of L1 between fresh tissue and formalin-fixed paraffin-embedded tissue samples depends on the CpG sites considered, and that the methylation status of L1 at CpG sites 1 and 4 combined could be utilized as a prognostic parameter for advanced gastric cancers.

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Long Interspersed Nucleotide Element 1 Hypomethylation Is Associated With Poor Prognosis of Lung Adenocarcinoma

Cited by 36 publications

References 35 publications

Alu and LINE-1 Hypomethylation Is Associated with HER2 Enriched Subtype of Breast Cancer

Alu and LINE-1 Hypomethylation Is Associated with HER2 Enriched Subtype of Breast Cancer

Densely ionizing radiation affects DNA methylation of selective LINE-1 elements

Methylation status of long interspersed element-1 in advanced gastric cancer and its prognostic implication

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