ReviewDNA methylation patterns in lung carcinomas
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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2022, European Journal of CancerCitation Excerpt :Furthermore, evidence shows these can negatively affect clinical outcomes, including overall survival, progression-free disease interval (PFI) and/or therapeutic response in patients with lung cancer [10,11]. Some epigenome-wide studies have identified several epigenetic aberrations in human lung tumours highlighting DNA hypermethylation at gene promoter sequences, controlling the expression of homeobox-related genes (HOX), which code for HOX transcriptions factors, which include, among others, MSX1, OTX1, OSR1, IRX2, PAX6 [12], SIX, LHX, PAX, DLX, and ENGRAILED [13], as well as some HOXA cluster genes, such as HOXA7 and HOXA9 [14]. Considering that some HOX-genes transcription factors have been proposed as potential biomarkers for early diagnosis and/or clinical therapeutic prognoses, it is likely that these factors could play a significant role in resistance mechanisms to oncological therapy displayed by lung cancer cells [15–17].
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