DNA methyltransferases messenger RNA expression and aberrant methylation of CpG islands in non-small-cell lung cancer: association and prognostic value.
BACKGROUND
A significant association between aberrant methylation in regulatory regions of tumor suppressor genes and clinical outcome in various different cancer types has been described. The molecular events for this epigenetic alteration still remain unknown. Evidence suggests that overexpression of DNA methyltransferases (DNMTs) is one potential mechanism for hypermethylation.


METHODS
Therefore, we investigated the influence of gene expression levels of the 3 DNMT isoforms (DNMT1, DNMT3a, and DNMT3b) and the hypermethylation of adenomatous polyposis coli (APC), the death-associated protein kinase (DAPK), glutathione S-transferase Pi (GSTPI), and the DNA repair gene O6-methylguanine DNA transferase (MGMT) in the pathogenesis and prognosis of patients with non-small cell lung cancer and determined their association to each other. Using a quantitative real-time reverse-transcriptase polymerase chain reaction, we measured messenger RNA expression of DNMT1, DNMT3a, and DNMT3b and DNA hypermethylation of APC, DAPK, GSTPI, and MGMT in 91 matching tumor and nonmalignant lung tissue samples from patients with curatively resected non-small-cell lung cancer.


RESULTS
In tumor tissue, the expression of all 3 DNMT isoforms was significantly higher compared with matched normal-appearing tissue (P < 0.001). Hypermethylation in tumor tissue was found in 95% for APC, in 92% for DAPK, in 18% for GSTPI, and in 38% for MGMT.


CONCLUSIONS
No correlation was found between the DNMT messenger RNA expression and DNA hypermethylation status in tumor tissues. Multivariate analysis revealed DNA hypermethylation status and TNM stage as independent prognostic factors.
Vallböhmer
Daniel
D
Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, USA. daniel.vallboehmer@freenet.de
Brabender
Jan
J
Yang
Dongyun
D
Schneider
Paul M
PM
Metzger
Ralf
R
Danenberg
Kathleen D
KD
Hölscher
Arnulf H
AH
Danenberg
Peter V
PV
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism; D018899:CpG Islands; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D015254:DNA Modification Methylases / Q000235:genetics*; D064550:Death-Associated Protein Kinases; D005260:Female; D017491:Genes, APC; D051549:Glutathione S-Transferase pi / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics; D000097584:DNA Methyltransferase 3B
D051017:Apoptosis Regulatory Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D015254:DNA Modification Methylases; D064550:Death-Associated Protein Kinases; D051549:Glutathione S-Transferase pi; D019853:O(6)-Methylguanine-DNA Methyltransferase; D012333:RNA, Messenger; D012097:Repressor Proteins; D000097584:DNA Methyltransferase 3B; C411744:DMAP1 protein, human; C000717967:DNMT3A protein, human; C496556:GSTP1 protein, human