Hypomethylation of Alu repetitive elements in esophageal mucosa, and its potential contribution to the epigenetic field for cancerization

Matsuda, Yasunori; Yamashita, Satoshi; Lee, Yi–Chia; Niwa, Tohru; Yoshida, Takeichi; Gyobu, Ken; Igaki, Hiroyasu; Kushima, Ryoji; Lee, Shigeru; Wu, Ming–Shiang; Osugi, Harushi; Suehiro, Shigefumi; Ushijima, Toshikazu

doi:10.1007/s10552-012-9955-4

Cited by 20 publications

(18 citation statements)

References 35 publications

(41 reference statements)

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“…Among Mexican-American children in rural California, a 1-log increase in maternal serum o,p´- DDT levels was associated with a reduced ALU methylation of 0.37% (Huen et al 2014). Contrast these differences with the reductions that could be observed comparing pathologically normal and tumor tissues, where differences can be 5–20% for LINE-1 (Cho et al 2010; Matsuda et al 2012; Stricker et al 2012; Zhang et al 2012) and 5–10% for Alu (Cho et al 2010; Matsuda et al 2012). In cancer, this marked hypomethylation of repetitive elements is thought to contribute to widespread genomic instability, which is a hallmark of most malignancies, but the functional importance of relatively small differences in these repetitive elements observed in nonpathologic tissues remains an outstanding question (reviewed by Nelson et al 2011).…”

Section: Investigating the Functional Relevance Of Replicated Locimentioning

confidence: 85%

Small-Magnitude Effect Sizes in Epigenetic End Points are Important in Children’s Environmental Health Studies: The Children’s Environmental Health and Disease Prevention Research Center’s Epigenetics Working Group

Breton

Marsit

Faustman

et al. 2017

Environ Health Perspect

241

159

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Background:Characterization of the epigenome is a primary interest for children’s environmental health researchers studying the environmental influences on human populations, particularly those studying the role of pregnancy and early-life exposures on later-in-life health outcomes.Objectives:Our objective was to consider the state of the science in environmental epigenetics research and to focus on DNA methylation and the collective observations of many studies being conducted within the Children’s Environmental Health and Disease Prevention Research Centers, as they relate to the Developmental Origins of Health and Disease (DOHaD) hypothesis.Methods:We address the current laboratory and statistical tools available for epigenetic analyses, discuss methods for validation and interpretation of findings, particularly when magnitudes of effect are small, question the functional relevance of findings, and discuss the future for environmental epigenetics research.Discussion:A common finding in environmental epigenetic studies is the small-magnitude epigenetic effect sizes that result from such exposures. Although it is reasonable and necessary that we question the relevance of such small effects, we present examples in which small effects persist and have been replicated across populations and across time. We encourage a critical discourse on the interpretation of such small changes and further research on their functional relevance for children’s health.Conclusion:The dynamic nature of the epigenome will require an emphasis on future longitudinal studies in which the epigenome is profiled over time, over changing environmental exposures, and over generations to better understand the multiple ways in which the epigenome may respond to environmental stimuli.Citation:Breton CV, Marsit CJ, Faustman E, Nadeau K, Goodrich JM, Dolinoy DC, Herbstman J, Holland N, LaSalle JM, Schmidt R, Yousefi P, Perera F, Joubert BR, Wiemels J, Taylor M, Yang IV, Chen R, Hew KM, Freeland DM, Miller R, Murphy SK. 2017. Small-magnitude effect sizes in epigenetic end points are important in children’s environmental health studies: the Children’s Environmental Health and Disease Prevention Research Center’s Epigenetics Working Group. Environ Health Perspect 125:–526; http://dx.doi.org/10.1289/EHP595

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Section: Investigating the Functional Relevance Of Replicated Locimentioning

confidence: 85%

Small-Magnitude Effect Sizes in Epigenetic End Points are Important in Children’s Environmental Health Studies: The Children’s Environmental Health and Disease Prevention Research Center’s Epigenetics Working Group

Breton

Marsit

Faustman

et al. 2017

Environ Health Perspect

241

159

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“…Different studies have already shown the hypomethylation of the LINE1 (long interspersed nucleotide element 1) in ESCC [54–57] and although this methylation profile was not correlated with tumour staging [57], Iwagami et al [56] showed a correlation with prognosis. Besides LINE1, the methylation status of Alu repeats was also investigated in ESCC [55]. In this study, not only the tumours showed lower methylation levels, but also their normal counterparts, in comparison with the oesophageal mucosa from healthy individuals.…”

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confidence: 99%

The potential of molecular markers to improve interventions through the natural history of oesophageal squamous cell carcinoma

et al. 2013

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EC (oesophageal cancer) is one of the ten most frequent and fatal tumours worldwide and ESCC (oesophageal squamous cell carcinoma) accounts for about 80% of the cases. The first symptoms of ESCC arise late during the progression of the disease and, therefore, the diagnosis is usually done in advanced stages. This leads to an inefficient treatment and consequently to a poor prognosis. Thus, a comprehensive knowledge of ESCC biology is of major importance to identify risk factors, especially in high-incidence areas and biomarkers which could enable ESCC prevention and interventions throughout the natural history of the disease. In this review, we present the current knowledge regarding ESCC aetiology as well as the different genetic and epigenetic alterations already described in this tumour. We also discuss how these alterations could be used to anticipate ESCC diagnosis as well as how they can help improving treatment. A molecular natural history of the disease is proposed pointing out potential markers that may improve interventions at different points of ESCC development. Only when the different layers of complexity behind this tumour are elucidated, it will be possible to successfully perform prevention at different levels.

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“…According to the hypothesis, precancerous lesions arise from normal esophageal epithelial surface subsequent of protracted carcinogens exposure and gradually develop into multiple discontinuous squamous cell carcinomas, as a reflection of the aberrant gene expression . Previous studies have addressed that field carcinogenesis in the digestive epithelium is characterized by global hypomethylation . Besides, p53, p16, IRF, mitochondrial DNA, and microsatellite instability are also involved.…”

Section: Discussionmentioning

confidence: 99%

“…The heterogeneity of the p53 gene mutation was observed by means of laser capture microdissection techniques. Other researchers identified global hypomethylation in the multiple ESCCs, and even in the noncancerous background mucosae . However, few studies focus on the functions of long noncoding RNAs (lncRNAs) in the development of multiple ESCCs.…”

Section: Introductionmentioning

confidence: 99%

Differential expression profiles of long noncoding RNAs in synchronous multiple and solitary primary esophageal squamous cell carcinomas: A microarray analysis

Qiu

et al. 2018

J of Cellular Biochemistry

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As a unique subtype of esophageal cancer, synchronous multiple primary esophageal squamous cell carcinomas (ESCCs) mostly occur in Asian patients with alcohol and/or tobacco abuse, or with a family history of cancer. Multiple ESCCs are associated with poor clinical outcomes. Growing evidence has addressed that long noncoding RNAs (lncRNAs) are involved in the carcinogenesis of various malignancies. We compared the lncRNA and messenger RNA (mRNA) profiles between solitary and multiple ESCC tissues through microarray analysis, aiming at studying their different mechanisms in tumor development. As a result, in multiple ESCCs, a total of 5257 lncRNAs and 3371 mRNAs were consistently differentially expressed compared with solitary ESCC, including 2986 upregulated and 2271 downregulated lncRNAs, and 2313 upregulated, and 1058 downregulated mRNAs. We validated the results in four differentially expressed lncRNAs using quantitative real‐time polymerase chain reaction. There were 38 and 20 pathways significantly related to up‐ and downregulated transcripts. The pathways associated with mostly enriched up‐ and downregulated mRNAs were hsa01200 (carbon metabolism) and hsa05221 (acute myeloid leukemia‐ homo sapiens [human]). Gene ontology analysis suggested that upregulated and downregulated mRNAs were mainly enriched in bounding membrane of organelle involved in the cellular component and positive regulation of transport involved in the biological process. Further analysis identified 189 differentially expressed paired antisense lncRNAs and relative sense mRNA, as well as 2134 differentially expressed long intergenic noncoding RNAs and their adjacent mRNA pairs. In conclusion, the aberrantly expressed lncRNAs might play a role in the carcinogenesis of multiple ESCCs and could be candidates as diagnostic biomarkers and therapeutic targets.

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Hypomethylation of Alu repetitive elements in esophageal mucosa, and its potential contribution to the epigenetic field for cancerization

Abstract: This is the first study to show the presence of global hypomethylation in ESCCs, and even in their non-cancerous background mucosae. Alu hypomethylation might reflect the severity of an epigenetic field for cancerization.

Cited by 20 publications

References 35 publications

Small-Magnitude Effect Sizes in Epigenetic End Points are Important in Children’s Environmental Health Studies: The Children’s Environmental Health and Disease Prevention Research Center’s Epigenetics Working Group

Small-Magnitude Effect Sizes in Epigenetic End Points are Important in Children’s Environmental Health Studies: The Children’s Environmental Health and Disease Prevention Research Center’s Epigenetics Working Group

The potential of molecular markers to improve interventions through the natural history of oesophageal squamous cell carcinoma

Differential expression profiles of long noncoding RNAs in synchronous multiple and solitary primary esophageal squamous cell carcinomas: A microarray analysis

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