Cancer Letters

Cancer Letters

Volume 301, Issue 1, 1 February 2011, Pages 7-16
Cancer Letters

Mini-review
DNA methylation in thoracic neoplasms

https://doi.org/10.1016/j.canlet.2010.10.017Get rights and content

Abstract

Thoracic neoplasms, which include lung cancers, esophageal carcinoma, and thymic epithelial tumors, are the leading causes of tumor-related death and a major health concern worldwide. The development of neoplasms is a multistep process involving both genetic and epigenetic alterations. A growing body of research provides evidence that aberrant DNA methylation, including DNA hypermethylation in promoter regions, global DNA hypomethylation and the overexpression of DNA methyltransferases, plays an important role in tumorigenesis. In this review, we summarize published observations of methylation pattern disruptions in thoracic tumors, and discuss how these abnormalities contribute to the development of cancers. We review recent findings showing that suppressing the activity of the DNA methylating enzymes DNMTs can have potent anti-cancer effects, and discuss the possibility of developing novel therapies for thoracic tumors based on DNMT inhibition.

Introduction

Thoracic neoplasms, including lung cancer, esophageal carcinoma, and thymic epithelial tumors (TETs), are the leading cause of tumor-related death and a major health concern worldwide [1], [2], [3], [4], [5]. Prevention, diagnosis, treatment, and prognosis of these tumors are challenging, emphasizing the need for developing new diagnostic and therapeutic strategies. Surgical tumor removal is currently the most commonly employed treatment option. However, the value of surgery is limited by the fact that it depends strongly on early diagnosis, and current screening methods – based on testing for radiological and clinical features – are either too costly or not sensitive enough to routinely detect early stage thoracic neoplasms [6], [7], [8], [9], [10], [11]. The development of alternative screening tests would thus improve the clinical management of thoracic neoplasms and improve patient outcomes.

A number of molecular features have been associated with the development and progression of thoracic neoplasms. In addition to genetic changes, including gene mutations, loss of heterozygosity or homozygous deletions, and chromosomal rearrangements [2], [12], characteristic epigenetic alterations have been found to be associated with tumorigenesis. These findings have broadened our understanding of non-genetic mechanisms underlying thoracic neoplasms and their relationship with environmental susceptibility factors. Furthermore, specific changes in epigenetic profiles have been associated with early stages of tumor development, and thus have the potential to be used as markers for screening and diagnosis [13], [14]. Moreover, since epigenetic alterations are reversible, therapeutic restoration of epigenetic states may provide a new avenue for the development of novel anti-cancer treatments [15], [16], [17], [18]. In this review, we explore the role of epigenetic alterations in the onset and progression of thoracic neoplasms, as well as the potential utility of characteristic changes in DNA methylation patterns for the development for diagnostic tests and therapeutic interventions.

Epigenetic traits include DNA methylation and histone modifications. The control of these is important for proper cellular function, and is therefore critical for normal development and health [19]. Alterations to the levels of DNA and histone modifications, can affect the transcription of genes involved in the regulation of cell growth, differentiation, transformation, and apoptosis. Not surprisingly, aberrant epigenetic regulation has also been found to be an important driving force in the initiation and progression of cancer [20], [21]. In this review, we provide an overview of the relationship between epigenetic alterations, especially DNA methylation, and the development of thoracic neoplasms.

Methylation of deoxycytosine bases in CG pairs has a profound effect on gene expression. DNA methyltransferase (DNMT) enzymes establish and maintain methylation patterns by catalyzing the addition of a methyl group onto the fifth carbon of the pyrimidine ring of cytosine residues within CpG dinucleotides, forming 5-methylcytosine bases (5-MC; Fig. 1A). Alterations to CpG methylation patterns have been shown to contribute to cancer in two ways. First, hypermethylation of gene promoters or first exons can lead to transcriptional silencing. Notably, the expression of some tumor suppressor genes (TSGs) is affected in this manner in certain cancers (Fig. 1B; [22], [23], [24], [25]). Second, hypomethylation of intergenic and intronic sequences in proto-oncogene regions of the genome is believed to cause chromosomal instability [19], [26], [27], [28]. These alterations are often associated with changes in the expression of DNMT genes [29], [30]. Recent studies indicate that gene-specific hypermethylation, global DNA hypomethylation, and overexpression of DNMTs are early events in many human malignancies, including lung cancer, esophageal cancer and TETs [31], [32], [33]. Because these manifestations occur early in tumorigenesis and are characteristic of distinct cancer types, they could represent targets for early diagnosis, prevention, and treatment.

Section snippets

DNA hypermethylation and thoracic neoplasms

It is now recognized that not only genetic mechanisms, but also aberrant DNA methylation, can provide one or both of the hits postulated in Knudson’s two hit hypothesis for the inactivation of tumor-related genes [34]. DNA hypermethylation of promoter regions has been shown to be part of the mechanism by which TSGs are silenced in human cancers. Indeed, the average number of methylation-silenced genes in a single tumor is estimated to be approximately 400 [35]. Recent studies show that

Global DNA hypomethylation and thoracic neoplasms

In addition to loci-specific alterations of DNA methylation, global DNA hypomethylation is often a feature of tumorigenic cells [32], [88], [89], [90]. Although DNA hypomethylation in cancer tissue was first observed more than two decades ago [91], [92] and may be linked to carcinogenesis [93], the exact mechanism and biological significance of this association remains poorly understood [19]. A recent study demonstrated that the loss of DNA methylation in cancer may have two important

DNMTs and thoracic neoplasms

In mammalian genomes, there are three DNMT genes; DNMT3a and DMMT3b are responsible for de novo methylation and modify unmethylated DNA, whereas DNMT1 is thought to be responsible for maintaining methylation patterns by acting on hemi-methylated DNA [99]. A number of studies have reported that DNMT activity is increased in cancer cells, and may be related to tumor aggressiveness and poor patient prognosis [100], [101], [102], [103], [104]. In particular, Lin et al. investigated the upregulation

Conclusion

Tumorigenesis is a multistep process involving the accumulation of deleterious genetic as well as epigenetic changes. Aberrant DNA methylation has been repeatedly observed in thoracic neoplasms, particularly in lung cancer, esophageal carcinoma, and TETs. It is also now recognized that promoter hypermethylation of TSGs, global DNA hypomethylation, and over expression of DNMTs are all important events in the progression of tumorigenesis. These findings provide not only new insights into the

Conflicts of interest

There is no any financial/commercial conflicts of interests involving in this study.

References (130)

  • N. Shivapurkar et al.

    Application of a methylation gene panel by quantitative PCR for lung cancers

    Cancer Lett.

    (2007)
  • R. Dammann et al.

    CpG island methylation and expression of tumour-associated genes in lung carcinoma

    Eur. J. Cancer

    (2005)
  • J.C. Park et al.

    Epigenetic silencing of human T (Brachyury homologue) gene in non-small-cell lung cancer

    Biochem. Biophys. Res. Commun.

    (2008)
  • P.H. Lo et al.

    Reduced expression of RASSF1A in esophageal and nasopharyngeal carcinomas significantly correlates with tumor stage

    Cancer Lett.

    (2007)
  • Z. Liu et al.

    5-Aza-2′-deoxycytidine induces retinoic acid receptor-beta(2) demethylation and growth inhibition in esophageal squamous carcinoma cells

    Cancer Lett.

    (2005)
  • L.J. Hardie et al.

    p16 Expression in Barrett’s esophagus and esophageal adenocarcinoma: association with genetic and epigenetic alterations

    Cancer Lett.

    (2005)
  • D. Lardinois et al.

    Prognostic relevance of Masaoka and Muller–Hermelink classification in patients with thymic tumors

    Ann. Thorac. Surg.

    (2000)
  • A. Zettl et al.

    Recurrent genetic aberrations in thymoma and thymic carcinoma

    Am. J. Pathol.

    (2000)
  • Y. Hirose et al.

    Aberrant methylation of tumour-related genes in thymic epithelial tumours

    Lung Cancer

    (2009)
  • A.S. Wilson et al.

    DNA hypomethylation and human diseases

    Biochim. Biophys. Acta

    (2007)
  • A.D. Riggs et al.

    5-Methylcytosine, gene regulation, and cancer

    Adv. Cancer Res.

    (1983)
  • C.J. Piyathilake et al.

    Altered global methylation of DNA: an epigenetic difference in susceptibility for lung cancer is associated with its progression

    Hum. Pathol.

    (2001)
  • A. Jemal et al.

    Cancer statistics, 2009

    CA Cancer J. Clin.

    (2009)
  • P.C. Enzinger et al.

    Esophageal cancer

    New Engl. J. Med.

    (2003)
  • Y. Shimosato

    Controversies surrounding the subclassification of thymoma

    Cancer

    (1994)
  • Y. Honglin et al.

    The correlation of the World Health Organization histologic classification of thymic epithelial tumors and its prognosis: a clinicopathologic study of 108 patients from China

    Int. J. Surg. Pathol.

    (2009)
  • D.E. Midthun

    Caution: screening for lung cancer

    Expert. Rev. Respir. Med.

    (2009)
  • U. Pastorino

    Lung cancer screening

    Br. J. Cancer

    (2010)
  • K. Kaneko

    Thoracoscopic surgery

    Kyobu Geka

    (2009)
  • X. Chen et al.

    Esophageal adenocarcinoma: a review and perspectives on the mechanism of carcinogenesis and chemoprevention

    Carcinogenesis

    (2001)
  • R.P. Arasaradnam et al.

    A review of dietary factors and its influence on DNA methylation in colorectal carcinogenesis

    Epigenetics

    (2008)
  • M. Vaid et al.

    Surfactant protein DNA methylation: a new entrant in the field of lung cancer diagnostics? (Review)

    Oncol Rep.

    (2009)
  • C. Long et al.

    Promoter hypermethylation of the RUNX3 gene in esophageal squamous cell carcinoma

    Cancer Invest.

    (2007)
  • M. Fabbri et al.

    MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B

    Proc. Natl. Acad. Sci. USA

    (2007)
  • Y. Oki et al.

    Review: recent clinical trials in epigenetic therapy

    Rev. Recent Clin. Trials

    (2006)
  • Y. Kondo et al.

    DNA methylation profiling in cancer

    Expert Rev. Mol. Med.

    (2010)
  • M. Ehrlich

    DNA methylation in cancer: too much, but also too little

    Oncogene

    (2002)
  • Q. Gan et al.

    Concise review: epigenetic mechanisms contribute to pluripotency and cell lineage determination of embryonic stem cells

    Stem Cells

    (2007)
  • K. Shima et al.

    Prognostic significance of CDKN2A (p16) promoter methylation and loss of expression in 902 colorectal cancers: Cohort study and literature review

    Int. J. Cancer

    (2010)
  • G. Deng et al.

    Regional hypermethylation and global hypomethylation are associated with altered chromatin conformation and histone acetylation in colorectal cancer

    Int. J. Cancer

    (2006)
  • Y. Kondo et al.

    Epigenetic changes in colorectal cancer

    Cancer Metast. Rev.

    (2004)
  • D.S. Kim et al.

    Aberrant methylation of E-cadherin and H-cadherin genes in nonsmall cell lung cancer and its relation to clinicopathologic features

    Cancer

    (2007)
  • K. Matsuzaki et al.

    The relationship between global methylation level, loss of heterozygosity, and microsatellite instability in sporadic colorectal cancer

    Clin. Cancer Res.

    (2005)
  • A. Eden et al.

    Chromosomal instability and tumors promoted by DNA hypomethylation

    Science

    (2003)
  • C.M. Tuck-Muller et al.

    DNA hypomethylation and unusual chromosome instability in cell lines from ICF syndrome patients

    Cytogenet. Cell Genet.

    (2000)
  • E. Arai et al.

    Regional DNA hypermethylation and DNA methyltransferase (DNMT) 1 protein overexpression in both renal tumors and corresponding nontumorous renal tissues

    Int. J. Cancer

    (2006)
  • C. Chen et al.

    Aberrant DNA methylation in thymic epithelial tumors

    Cancer Invest.

    (2009)
  • I.P. Pogribny et al.

    DNA hypomethylation in the origin and pathogenesis of human diseases

    Cell Mol. Life Sci.

    (2009)
  • T.A. Rauch et al.

    High-resolution mapping of DNA hypermethylation and hypomethylation in lung cancer

    Proc. Natl. Acad. Sci. USA

    (2008)
  • P.A. Jones et al.

    Cancer epigenetics comes of age

    Nat. Genet.

    (1999)
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