DNA methylation patterns in lung carcinomas

doi:10.1016/j.semcancer.2009.02.008

Seminars in Cancer Biology

Volume 19, Issue 3, June 2009, Pages 181-187

https://doi.org/10.1016/j.semcancer.2009.02.008 Get rights and content

Abstract

The genome of epithelial tumors is characterized by numerous chromosomal aberrations, DNA base sequence changes, and epigenetic abnormalities. The epigenome of cancer cells has been most commonly studied at the level of DNA CpG methylation. In squamous cell carcinomas of the lung, CpG methylation patterns undergo substantial changes relative to normal lung epithelium. Using a genome-scale mapping technique for CpG methylation (MIRA-chip), we characterized CpG island methylation and methylation patterns of entire chromosome arms at a level of resolution of ∼100 bp. In individual stage I lung carcinomas, several hundred and probably up to a thousand CpG islands become methylated. Interestingly, a large fraction (almost 80%) of the tumor-specifically methylated sequences are targets of the Polycomb complex in embryonic stem cells. Homeobox genes are particularly overrepresented and all four HOX gene loci on chromosomes 2, 7, 12, and 17 are hotspots for tumor-associated methylation because of the presence of multiple methylated CpG islands within these loci. DNA hypomethylation at CpGs in squamous cell tumors preferentially affects repetitive sequence classes including SINEs, LINEs, subtelomeric repeats, and segmental duplications. Since these epigenetic changes are found in early stage tumors, their contribution to tumor etiology as well as their potential usefulness as diagnostic or prognostic biomarkers of the disease should be considered.

Section snippets

Mammalian DNA methylation

The only known enzymatic modification of DNA bases in mammalian cells is the post-replicative addition of a methyl group to position 5 of cytosines. The methylated cytosines are almost exclusively formed at the CpG (5′) dinucleotide sequence. CpG methylation is catalyzed by DNA methyltransferase proteins (DNMTs). DNA methyltransferase 1 (DNMT1) is responsible for faithful copying of the preexisting cellular DNA methylation patterns following DNA replication. DNMT3A and DNMT3B are primarily

DNA methylation changes in cancer

Changes in DNA methylation patterns are one of the most frequent events that occur in human tumors, and altered CpG methylation patterns discriminate tumor tissue from its nonmalignant counterpart tissue or normal adjacent tissue [10]. Two types of methylation changes are most commonly observed: hypermethylation of CpG islands and a more global hypomethylation of DNA in tumors. The literature now contains thousands of reports that have documented methylation of CpG islands associated with

DNA methylation and lung cancer

Lung cancer is the leading cause of cancer death in the United States and most other countries [43]. Its causation by cigarette smoking is unquestionable [44]. Lung cancer accounts for about 30% of all deaths from cancer and at least 1.5 million annual deaths from lung cancer are projected worldwide by 2010. The high (>80%) mortality rate associated with lung cancer is at least in part related to suboptimal therapeutic strategies and the lack of an efficient screening approach for early

DNA methylation detection methods

The field of DNA methylation analysis is moving fast towards genome-wide characterization rather than studying methylation of individual genes in tumors. Diverse technical approaches for large-scale methylation analysis have been developed [62]. The first group of techniques is based on methylation-sensitive restriction endonuclease cleavage of the target sequences (e.g., HpaII, NotI) [63], [46], [64]. These techniques are useful but are limited by the occurrence of the respective recognition

Analysis of lung carcinoma genomes by MIRA-chip analysis

Initially, we used spotted CpG island arrays to analyze methylation patterns of the lung cancer cell line A549. Using the data obtained from such arrays, a list of genes was compiled that show hypermethylation in A549 lung cancer cells relative to normal human bronchial epithelial (NHBE) cells [78]. Cancer cell line-specific methylation and lack of methylation in NHBE cells was confirmed by bilsulfite-based analysis for several of the targets identified by the microarrays. Among the 25 targets

The significance of epigenetic changes in cancer

From recent large scale sequencing of human tumor DNA, it has become clear that recurrent changes in the DNA sequence, such as point mutations, insertions, or deletions within specific genes are quite uncommon in human tumors [82], [83]. Most mutations seem to be rather stochastic and are rarely selected in specific genes (exception TP53, RAS genes, a few others). Chromosomal aberrations involving loss of genetic material, e.g. loss of heterozygosity, chromosomal deletions, copy number changes,

The challenges that lie ahead

i)
The analysis of lung cancer epigenomes should be expanded to include the determination of genome-wide changes of histone modification patterns. How are these changes in chromatin correlated to changes in the DNA methylation pattern?
ii)
It is important to establish a temporal sequence of epigenomic alterations during the initiation and progression of lung squamous cell cancers. Early lesions including hyperplasia, dysplasia and carcinoma in situ should be analyzed to see which types of epigenetic

Conflict of interest

The authors declare that there are no conflicts of interest.

Acknowledgements

The work of the authors has been supported by grants from the National Cancer Institute to G.P.P. (CA084469 and CA128495).

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ReviewDNA methylation patterns in lung carcinomas

Abstract

Section snippets

Mammalian DNA methylation

DNA methylation changes in cancer

DNA methylation and lung cancer

DNA methylation detection methods

Analysis of lung carcinoma genomes by MIRA-chip analysis

The significance of epigenetic changes in cancer

The challenges that lie ahead

Conflict of interest

Acknowledgements

Curr Top Dev Biol

Cell

Curr Opin Genet Dev

Cell

Cell

Cell

Biochem Biophys Res Commun

Biochim Biophys Acta

Cancer Cell

Crit Rev Oncol Hematol

Cancer Lett

Chest

Eur J Cancer

Cancer Cell

Genomics

J Biol Chem

Lab Invest

Cell

Maintenance and regulation of DNA methylation patterns in mammals

Biochem Cell Biol

A Dnmt2-like protein mediates DNA methylation in Drosophila

Development

Methylation of tRNAAsp by the DNA methyltransferase homolog Dnmt2

Science

CpG-rich islands and the function of DNA methylation

Nature

Mutagenesis at methylated CpG sequences

Curr Top Microbiol Immunol

The power and the promise of DNA methylation markers

Nat Rev Cancer

Gene-promoter hypermethylation as a biomarker in lung cancer

Nat Rev Cancer

Detection and interpretation of altered methylation patterns in cancer cells

Nat Rev Cancer

Changes in methylation of cattle lymphocyte DNA during chronic lymphoid leukosis

Biokhimiya

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

Oncogene

Analysis of repetitive element DNA methylation by MethyLight

Nucleic Acids Res

Genome-wide hypomethylation in human glioblastomas associated with specific copy number alteration, methylenetetrahydrofolate reductase allele status, and increased proliferation

Cancer Res

Chromosomal instability correlates with genome-wide DNA demethylation in human primary colorectal cancers

Cancer Res

LINE-1 hypomethylation in cancer is highly variable and inversely correlated with microsatellite instability

PLoS ONE

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

Proc Natl Acad Sci USA

Induction of tumors in mice by genomic hypomethylation

Science

Hypomethylation of classical satellite DNA and chromosome instability in lymphoblastoid cell lines

Hum Genet

Promoter hypomethylation of the LINE-1 retrotransposable elements activates sense/antisense transcription and marks the progression of chronic myeloid leukemia

Oncogene

Opposing effects of DNA hypomethylation on intestinal and liver carcinogenesis

Proc Natl Acad Sci USA

Activation and transposition of endogenous retroviral elements in hypomethylation induced tumors in mice

Oncogene

Predicting aberrant CpG island methylation

Proc Natl Acad Sci USA

Evidence for an instructive mechanism of de novo methylation in cancer cells

Nat Genet

Hypermethylation trigger of the glutathione-S-transferase gene (GSTP1) in prostate cancer cells

Oncogene

Chromatin inactivation precedes de novo DNA methylation during the progressive epigenetic silencing of the RASSF1A promoter

Mol Cell Biol

Review
DNA methylation patterns in lung carcinomas