[Aberrant promoter methylation of tumor suppressor genes in serum from lung cancer patients: frequency and correlation with clinicopathological characteristics].
OBJECTIVE
The aim of this study was to determine aberrant promoter methylation of tumor suppressor genes in genomic serum DNA from lung cancer patients and to evaluate the association between methylation of genes and clinicopathological characteristics.


METHODS
Genomic serum DNA from 46 lung cancer patients and 14 healthy control persons was examined. Nested methylation-specific PCR approach was used for detection of methylated genes in serum.


RESULTS
Aberrant promoter methylation in serum from lung cancer patients was detected in 2.3% (1/43) for O6-methylguanine-DNA-methyltransferase, in 11.1% (5/45) for p16INK4a, in 41.3% (19/46) for retinoic acid receptor beta, in 4.5% (2/44) for RAS association domain family 1A, in 40.9% (18/44) for fragile histidine triad, in 34.9% (15/45) for p14(ARF), in 6.5% (3/46) for adenomatous polyposis coli 1A, in 78.1% (25/32) for Ecad, in 5.7% (2/35) for adenomatous polyposis coli 1B, in 0% (0/36) for death associated protein kinase. None of the death associated protein kinase, O6-methylguanine-DNA-methyltransferase, p16INK4a, fragile histidine triad or adenomatous polyposis coli 1A promoter regions were positive for methylation in serum DNA from healthy persons. A total of 78.3% of the samples from lung cancer patients had methylation in at least one of the genes tested. The methylation status of fragile histidine triad was associated with that of p14ARF(p=0.021), as was retinoic acid receptor beta--with that of adenomatous polyposis coli 1A (p=0.04). Methylation of adenomatous polyposis coli 1A was detected more frequently in tumor with pleura involvement (p=0.079), retinoic acid receptor beta was observed more frequently in undifferentiated tumor than in better-differentiated tumor (p=0.029). The methylation status of RAS association domain family 1A and fragile histidine triad showed a tendency to be associated with an advanced tumor size. In addition, tumors with an advanced pathological stage showed epigenetic alteration of the RAS association domain family 1A promoter with a higher frequency. The methylation index was also associated with an advanced tumor size (p=0.033).


CONCLUSIONS
Approximately 80% of the samples from lung cancer patients had methylation of the tumor suppressor gene and it might be associated with more aggressive tumor. Detection of epigenetic alterations in serum may provide basis for the early and noninvasive lung cancer diagnosis and customized therapy.
Zemaitis
Marius
M
Department of Pulmonology and Immunology, Institute for Biomedical Research, Kaunas University of Medicine, Eiveniu 2, 50009 Kaunas, Lithuania. mzemaiti@kmu.lt
Rieger
Norman
N
Fischer
Jürgen Richard
JR
Sakalauskas
Raimundas
R
Malakauskas
Kestutis
K
Lahm
Harald
H
D000293:Adolescent; D000368:Aged; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000097:blood; D003627:Data Interpretation, Statistical; D004586:Electrophoresis; D005260:Female; D016147:Genes, Tumor Suppressor; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic
D004273:DNA, Neoplasm