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At least 739 records · Page 41Linked to original sources
PubMed2003

Epigenetic silencing of multiple interferon pathway genes after cellular immortalization.

Abrogating cellular senescence is a necessary step in the formation of a cancer cell. Promoter hypermethylation is an epigenetic mechanism of gene regulation known to silence gene expression in carcinogenesis. Treatment of spontaneously immortal Li-Fraumeni fibroblasts with 5-aza-2'-deoxycytidine (5AZA-dC), an inhibitor of DNA methyltransferase (DNMT), induces a senescence-like state. We used microarrays containing 12 558 genes to determine the gene expression profile associated with cellular immortalization and also regulated by 5AZA-dC. Remarkably, among 85 genes with methylation-dependent downregulation (silencing) after immortalization, 39 (46%) are known to be regulated during interferon signaling, a known growth-suppressive pathway. This work indicates that gene silencing may be associated with an early event in carcinogenesis, cellular immortalization.

Antimetabolites, Antineoplastic↗
PubMed1996

Multicopy fimB gene expression in Escherichia coli: binding to inverted repeats in vivo, effect on fimA gene transcription and DNA inversion.

Transcription of fimA, the Escherichia coli gene encoding the type 1 fimbrial subunit protein, is driven by a promoter carried on a 314 bp segment of invertible DNA. We have discovered that overexpression of fimB, one of the genes required for inversion of this DNA element, results in transcriptional repression of fimA. Furthermore, under these conditions inversion ceases to be dependent on the integration host factor (IHF) or the leucine-responsive regulatory protein (LRP), cofactors hitherto considered to be essential for inversion. Inversion will even occur (albeit at a very low level) in the absence of both cofactors. The interaction of the fimB gene product with the invertible element was studied in vivo in the presence of single- and multicopy fimB genes. Dimethyl sulphoxide (DMS)-mediated methylation of DNA at the 9 bp inverted repeats, which flank the invertible element, was found to vary in the presence and absence of functional fimB. The DMS reactivity profile at the left-hand inverted repeat was similar with single or multicopy fimB. The corresponding profile at the right-hand inverted repeat varied with fimB copy number. As this repeat lies between the fimA promoter and open reading frame, FimB binding here is likely to modulate fimA transcription and vice versa.

Bacterial Proteins↗
PubMed2006

Mismatch repair and treatment resistance in ovarian cancer.

BACKGROUND: The treatment of ovarian cancer is hindered by intrinsic or acquired resistance to platinum-based chemotherapy. The aim of this study is to determine the frequency of mismatch repair (MMR) inactivation in ovarian cancer and its association with resistance to platinum-based chemotherapy. METHODS: We determined, microsatellite instability (MSI) as a marker for MMR inactivation (analysis of BAT25 and BAT26), MLH1 promoter methylation status (methylation specific PCR on bisulfite treated DNA) and mRNA expression of MLH1, MSH2, MSH3, MSH6 and PMS2 (quantitative RT-PCR) in 75 ovarian carcinomas and eight ovarian cancer cell lines RESULTS: MSI was detected in three of the eight cell lines i.e. A2780 (no MLH1 mRNA expression due to promoter methylation), SKOV3 (no MLH1 mRNA expression) and 2774 (no altered expression of MMR genes). Overall, there was no association between cisplatin response and MMR status in these eight cell lines. Seven of the 75 ovarian carcinomas showed MLH1 promoter methylation, however, none of these showed MSI. Forty-six of these patients received platinum-based chemotherapy (11 non-responders, 34 responders, one unknown response). The resistance seen in the eleven non-responders was not related to MSI and therefore also not to MMR inactivation. CONCLUSION: No MMR inactivation was detected in 75 ovarian carcinoma specimens and no association was seen between MMR inactivation and resistance in the ovarian cancer cell lines as well as the ovarian carcinomas. In the discussion, the results were compared to that of twenty similar studies in the literature including in total 1315 ovarian cancer patients. Although no association between response and MMR status was seen in the primary tumor the possible role of MMR inactivation in acquired resistance deserves further investigation.

Adaptor Proteins, Signal Transducing↗
PubMed2026

Somatic genetic alterations in pituitary neuroendocrine tumors.

The molecular characterization of pituitary neuroendocrine tumors (PitNETs) has progressed pronouncedly in recent years, unraveling the molecular pathways driving initiation and progression of different PitNET types and allowing a better understanding of their biology. The most frequent recurring somatic driver alterations were recognized in corticotroph PitNETs (USP8, USP48, BRAF) and somatotroph PitNETs (GNAS) and, much less frequently, in lactotroph PitNETs (SF3B1). Additional well-characterized somatic driver alterations, including TP53, ATRX, and DAXX, are enriched in aggressive corticotroph tumors. Identification of new molecular markers and delineation of their clinical phenotypes are enabling further subclassification of PitNETs based on tumor molecular profiles, with earlier recognition of more aggressive variants. These molecular markers also provide an opportunity for new targeted therapies. Beyond single-gene alterations, epigenetic modifications, such as DNA methylation, histone modifications, and noncoding RNA dysregulation, are emerging as important contributors to PitNET pathogenesis and potential therapeutic targets. Multi-omics approaches encompassing genomics, transcriptomics, epigenomics, and proteomics are transforming PitNET classification. In this review, we provide a comprehensive, data-driven update on somatic driver alterations, epigenetic alterations, converging signaling pathways, and the related emerging therapeutic targets in PitNETs, integrating pooled analyses from published cohorts.

Humans↗
PubMed2026

Development and preliminary validation of plasma cell-free DNA methylation-based diagnostic prediction model for colorectal cancer detection.

BACKGROUND: Colorectal cancer (CRC) is a common malignancy associated with genetic and epigenetic alterations. Several methylation biomarkers have been investigated for non-invasive CRC detection; however, their reported performance varies across clinical settings, and the detection of early-stage or precancerous disease and discrimination from non-malignant colorectal conditions remain challenging. This exploratory study aimed to identify reproducible CRC-associated plasma cell-free DNA (cfDNA) methylation regions and to develop and preliminarily evaluate diagnostic prediction model for distinguishing CRC from healthy controls and benign samples. METHODS: Public CRC tissue methylation datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were analyzed to identify reproducible CRC-associated methylation alterations. Plasma cfDNA methylation was profiled using methyl-CpG-binding-domain enrichment followed by paired-end sequencing in patients with CRC, patients with colorectal polyps, and healthy controls. After quality-control filtering, 30 CRC and healthy-control samples were randomly allocated at the participant level in a 7:3 ratio to a development set comprising 10 patients with CRC and 11 healthy controls and a held-out test set comprising 4 patients with CRC and 5 healthy controls. Hypermethylated regions were selected using least absolute shrinkage and selection operator (LASSO) logistic regression. The 12-region model was evaluated in the held-out test set and subsequently applied to 10 colorectal polyp samples without refitting or recalibration. RESULTS: Tissue methylation analysis identified reproducible CRC-associated alterations across independent datasets. In the plasma development set, 707 differentially methylated regions (DMRs) were identified between CRC and healthy-control samples, including 324 hypermethylated and 383 hypomethylated regions. LASSO regression selected a 12-region hypermethylation signature. In the held-out test set, the model achieved an area under the curve (AUC) of 0.85 [95% confidence interval (CI): 0.579-1.000]. At the development-set-derived threshold, sensitivity was 75.0% (3/4), specificity was 60.0% (3/5), and accuracy was 66.7% (6/9). When the original model was applied to colorectal polyp samples, model scores were significantly higher in both CRC and polyp samples than in healthy controls, while CRC samples showed a tendency toward higher scores than polyp samples. CONCLUSIONS: This exploratory study identified a 12-region plasma cfDNA hypermethylation signature associated with CRC and developed a LASSO-based diagnostic prediction model that showed preliminary discrimination between CRC and healthy controls in a small held-out test set. By integrating tissue methylation evidence with plasma cfDNA profiling, this study expands the repertoire of candidate region-level methylation markers for blood-based CRC detection.

Colorectal cancer (CRC)↗
PubMed2002

Remodeling of DNA methylation and phenotypic and transcriptional changes in synthetic Arabidopsis allotetraploids.

The joining of different genomes in allotetraploids played a major role in plant evolution, but the molecular implications of this event are poorly understood. In synthetic allotetraploids of Arabidopsis and Cardaminopsis arenosa, we previously demonstrated the occurrence of frequent gene silencing. To explore the involvement of epigenetic phenomena, we investigated the occurrence and effects of DNA methylation changes. Changes in DNA methylation patterns were more frequent in synthetic allotetraploids than in the parents. Treatment with 5-aza-2'-deoxycytidine, an inhibitor of DNA methyltransferase, resulted in the development of altered morphologies in the synthetic allotetraploids, but not in the parents. We profiled mRNAs in control and 5-aza-2'-deoxycytidine-treated parents and allotetraploids by amplified fragment length polymorphism-cDNA. We show that DNA demethylation induced and repressed two different transcriptomes. Our results are consistent with the hypothesis that synthetic allotetraploids have compromised mechanisms of epigenetic gene regulation.

Arabidopsis↗
PubMed2006

Pattern of expression of genes linked to epigenetic silencing in human breast cancer.

Epigenetic mechanisms such as DNA methylation are now recognized to play an important role in neoplasia. The aim of this study is to relate the pattern of expression of multiple cancer genes known to undergo epigenetic inactivation by promoter hypermethylation in breast cancer with histologic and outcome data. We used immunohistochemistry to study expression of the tumor suppressor gene p16, estrogen receptor (ER) alpha, ERbeta, progesterone receptor (PR), and the DNA repair gene MGMT (O6 -methylguanine-DNA methyltransferase) in a panel of 200 breast cancers. Methylation-specific polymerase chain reaction was used to confirm MGMT promoter methylation. Loss of expression of MGMT, ERalpha, ERbeta, PR, and p16 was observed in 19%, 24%, 13%, 40%, and 50% of cases, respectively. A significant correlation was seen between grade III tumor and loss of expression of ERalpha, ERbeta, PR (all P < .0001), and MGMT (P = .04), whereas loss of expression of p16 was associated with grades I and II tumors (P < .001). Cases that expressed 3 or less of the 5 proteins studied had significantly reduced survival (P = .0016). Methylation-specific polymerase chain reaction in a subset of 20 cancers showed DNA methylation associated with the loss of MGMT expression (P < .001). In conclusion, there is silencing of several key genes in breast cancer affecting molecular pathways involved in cell immortalization, DNA repair, and hormonal regulation, and this correlates significantly with risk of cancer-specific death. This expression profile could be linked to epigenetic events, and if so, these pathways have potential as targets for therapeutic strategies based on reversal of epigenetic silencing.

Adenocarcinoma↗
PubMed2004

The Werner syndrome protein confers resistance to the DNA lesions N3-methyladenine and O6-methylguanine: implications for WRN function.

The Werner syndrome (WS) protein (WRN), a DNA helicase/exonuclease, is required for genomic stability and avoidance of cancer. Current evidence suggests that WRN is involved in the resolution of stalled and/or collapsed replication forks. This function is indicated, in part, by replication defects in WS cells and by hypersensitivity to agents causing major structural aberrations in DNA that block replication. We show here that antisense suppression of WRN in two human glioma cell lines reproduces hallmarks of the drug cytotoxicity profile of WS cells, namely, hypersensitivity to 4-nitroquinoline 1-oxide, camptothecin and hydroxyurea. We also show that antisense-treated cells are hypersensitive to methyl-lexitropsin, a site-specific alkylating agent that produces mainly N3-methyladenine, a cytotoxic and replication-blocking lesion. Antisense-treated cells are hypersensitive to O(6)-methylguanine adducts as well, but only when repair by O(6)-methylguanine-DNA methyltransferase is lacking. Our results illustrate the drug sensitivity caused by deficiency of WRN in a uniform genetic background. They extend the WRN DNA damage sensitivity spectrum to methyl base adducts that can result in blocked replication, and suggest that WRN may be required for resumption of processive replication when incomplete repair of DNA damage leaves blocking lesions at forks. The evidence that highly disparate lesions fall within the purview of WRN, and that abrogating DNA repair can reveal dependence on WRN, suggests that WRN may protect the genome from the lethal, mutagenic and carcinogenic effects of widely diverse DNA damage arising from endogenous processes and environmental agents.

4-Nitroquinoline-1-oxide↗
PubMed1995

Proximity probing of Tet repressor to tet operator by dimethylsulfate reveals protected and accessible functions for each recognized base-pair in the major groove.

We have tracked the path of Tet repressor across the major groove in the complex with tet operator. This was done by a methylation protection analysis of nine tet operator mutants containing replacements by a G residue of each nucleotide in base-pairs important for Tet repressor recognition. We demonstrated sequence-specific binding of Tet repressor to these operator mutants using DNA retardation assays and the protection of the wild-type +2G residue from methylation. Hydroxyl radical cleavage protection analysis of the Tet repressor-tet operator complexes indicated identical, or at least very similar, locations of the DNA reading head across the major groove of wild-type and mutant operator DNA. Methylation protection occurred at the G residues in positions +3, +4, -5 and -6, whereas the G residues in the respective opposite strands showed enhanced methylation. These results show that most amino acid side-chains of Tet repressor are in close proximity to only one base of each base-pair in the major groove of tet operator. The Tet repressor mutant PS39 gave a changed methylation protection pattern at base-pair four of tet operator indicating that the residue at this position can contact either base at this base-pair depending on the amino acid side-chain present. Tet repressor mutants QA38 and TA40 with a loss of specificity phenotype gave the same methylation protection profile as wild-type TetR confirming that this experiment scores proximity rather than chemical interaction. The excellent agreement of these results with those obtained in genetic analyses demonstrates that this method yields a high-resolution proximity pattern of Tet repressor with tet operator and that it may be generally applicable for the analysis of protein-DNA complexes.

Base Composition↗
PubMed1996

Germ-line passage is required for establishment of methylation and expression patterns of imprinted but not of nonimprinted genes.

Embryonic stem (ES) cells homozygous for a disruption of the DNA (cytosine-5)-methyltransferase gene (Dnmt) proliferate normally with their DNA highly demethylated but die upon differentiation. Expression of the wild-type Dnmt cDNA in mutant male ES cells caused an increase in methylation of bulk DNA and of the Xist and Igf2 genes to normal levels, but did not restore the methylation of the imprinted genes H19 and Igf2r. These cells differentiated normally in vitro and contributed substantially to adult chimeras. While the Xist gene was not expressed in the remethylated male ES cells, no restoration of the normal expression profile was seen for H19, Igf2r, or Igf2. This indicates that ES cells can faithfully reestablish normal methylation and expression patterns of nonimprinted genes but lack the ability to restore those of imprinted genes. Full restoration of monoallelic methylation and expression was imposed on H19, Igf2, and Igf2r upon germ-line transmission. These results are consistent with the presence of distinct de novo DNA methyltransferase activities during oogenesis and spermatogenesis, which specifically recognize imprinted genes but are absent in the postimplantation embryo and in ES cells.

Alleles↗
PubMed2000

Correlation between DNA methylation and murine IFN-gamma and IL-4 expression.

In order to determine the possible role of DNA methylation as a regulatory mechanism for the restricted pattern of lymphokine production among differentiated Th(1)and Th(2)cells, we examined the extent of methylation of the interferon gamma (IFN-gamma) and the interleukin 4 (IL-4) genes in fresh activated murine Th(0), Th(1)and Th(2)cells, unstimulated naive T cells, B cells, bone marrow derived non-B non-T cells, thymocytes and liver. All of the CpG dinucleotides examined in the IL-4 and the IFN-gamma genes, were fully methylated over the body of the gene in all of the examined cells. However, analysis of the promoter regions of these genes revealed a different pattern. While the IL-4 promoter is fully methylated in all of the examined cells, two adjacent CpG dinucleotides near the initiation point of the IFN-gamma gene were unmethylated in all T cells, including 17-day-old fetal thymocytes. In contrast, B cells, bone marrow non-B non-T cells and liver cells displayed a full methylated profile of the IFNgamma promoter. These results suggest that the mutually exclusive pattern of IFNgamma and IL-4 production in Th(1)and Th(2)cells is not regulated by differential demethylation of these two genes.

Animals↗
PubMed1993

Genetic relationships among actinomycetes that produce the immunosuppressant macrolides FK506, FK520/FK523 and rapamycin.

A polyphasic taxonomic study was undertaken to establish the genetic and phenotypic relationships among six actinomycetes that produce the immunosuppressant macrolides FK506, FK520/FK523 and rapamycin. Chemotaxonomic studies reveal that all have Type I cell walls. Gas chromatography (GC) of fatty acid methyl esters revealed patterns consistent for strains of Streptomyces with 16:0 and 15:0 anteiso predominating. Principal component analysis of GC data revealed distinct profiles for each culture. Reciprocal DNA homology studies at Tm-25 showed the rapamycin-producing strain and one FK506-producing strain to have 38-50% homology with the type strain of Streptomyces hygroscopicus (ATCC 27438). The remaining strains exhibited 6-17% homology. To further explore the relationships among these strains all were probed for the presence of an O-methyltransferase gene specific to this biosynthetic pathway. Among the strains of interest, only Streptomyces hygroscopicus subsp. yakushimaensis, the patent strain for FK520/FK523, failed to hybridize with the probes.

Anti-Bacterial Agents↗
PubMed1973

Chromatographically fractionated complementary strands of Bacillus subtilis deoxyribonucleic acid: biological properties.

Biological, physical, and chromatographic properties of methylated albuminkieselguhr (MAK)-fractionated complementary strands, designated as light (L) and heavy (H), of Bacillus subtilis deoxyribonucleic acid (DNA) are presented. The pattern of transforming activity along the MAK elution profile of alkilidenatured DNA shows that the residually active molecules selectively fractionated ahead of the L strand fraction, whereas the most active self-annealed molecules fractionated preferentially at the trailing end of the H strand fraction. The restoration rate of transforming activity in the late-eluting H molecules was rapid and independent of concentration during the annealing reaction. The data suggest that the self-annealing activity in the H strand is due in part to the formation of intrastrand secondary structures. Hydroxyapatite chromatography of self-annealed L and H strands yielded a major fraction (I) of highly purified strand preparations devoid of transforming activity and hypochromicity, and a minor "nativelike" fraction (II). Sedimentation velocity measurements show that, in addition to the mutual complementary nature of the L and H fractions, they differ in molecular size and possibly configuration.

Bacillus subtilis↗
PubMed2004

Molecular profiling and classification of sporadic renal cell carcinoma by quantitative methylation analysis.

PURPOSE: Preoperative histologic classification of solid renal masses remains limited with current technology. We determine the utility of molecular profiling based on quantitative methylation analysis for characterization of sporadic renal cell carcinoma. EXPERIMENTAL DESIGN: Primary renal cell carcinomas representing three different histologic subtypes were obtained from a total of 38 patients who underwent radical nephrectomy for suspected malignant disease. Genomic DNA was isolated from tumors and was subjected to sodium bisulfite modification. The normalized index of methylation (NIM) for each sample was determined by quantitative real-time methylation-specific PCR at 17 different gene promoters. Hierarchical cluster analysis was performed by using an unsupervised neural network with binary tree topology. RESULTS: The majority of gene promoters that were analyzed in this study demonstrated very low levels of methylation (NIM <1.0). The RASSF1A gene promoter, however, was methylated in 30 of 38 (79%) cases. The frequency of RASSF1A methylation in papillary, clear-cell, and oncocytoma subtypes was 100, 90, and 25%, respectively. The highest levels of RASSF1A methylation were observed in the papillary (mean NIM = 78.9) and clear-cell (mean NIM = 13.4) subtypes. The vast majority of oncocytomas were completely unmethylated, and none demonstrated >1% methylation (mean NIM = 0.11). Hierarchical cluster analysis based on quantitative methylation levels resulted in stratification of sporadic renal cell carcinomas into their discrete histologic subtypes. CONCLUSIONS: Classification of sporadic renal cell carcinomas into histologic subtypes can be accomplished via multigene quantitative methylation profiling. Validation of this approach and selection of appropriate methylation markers may ultimately lead to use of this technology in the preoperative assessment of suspicious renal masses.

Aged↗
PubMed2002

Isolation of Carnobacterium piscicola from human pus--case report.

Carnobacterium piscicola was first described in 1984. These bacteria are often isolated from fish afflicted with bacterial infections. To date, there has been no reported isolation of this bacterium from human specimens. We report here the isolation of C. piscicola from the pus following traumatic amputation of the right hand in the wrist of a 35-year-old man. The traumatic amputation occurred with an industrial water sawmill. The identity of the human strain was determined biochemically, by 16S rDNA sequence similarity and by fatty-acid methyl-ester profile from bacterial cell.

Adult↗
PubMed2006

Quantitative analysis of promoter hypermethylation in multiple genes in osteosarcoma.

BACKGROUND: Osteosarcoma is the most common solid malignant diseases of childhood, occurring in approximately 6 children per million annually; however, to the authors' knowledge to date, the cause of osteosarcoma has remained mostly unknown. Genetic alterations of genes that are specific for osteosarcoma have not been identified. Genetic alternations in the status of DNA methylation, known as epigenetic alterations, are the most common molecular alterations in human neoplasia. Aberrant methylation in the promoter region of tumor-related genes is associated closely with epigenetically mediated gene silencing, which is a common feature in human tumors. METHODS: The authors analyzed CpG islands of 5 different gene loci for aberrant methylation profiles in 30 pairs of osteosarcoma and corresponding normal tissues by using the quantitative methylation-specific polymerase chain reaction method. The objectives of this study were to characterize the methylation changes in osteosarcoma more extensively and to identify epigenetic biomarkers that may be useful in the diagnosis and prevention of osteosarcoma. RESULTS: For the Ras effector homologue (RASSF1A), tissue inhibitor of metalloproteinase 3 (TIMP3), O-6-methylguanine DNA methyltransferase (MGMT), and death-associated protein kinase 1 (DAPK1) genes, significant differences were observed in the degree of hypermethylation between tumors and normal tissues (P < 0.01 and P < 0.001, respectively). Measurement of the cumulative multiple promoter hypermethylation revealed striking differences between tumor specimens and normal tissues (t = 7.31; P < .001). There also was a significant difference in the levels of DNA methylation between the metastatic and nonmetastatic high-grade osteosarcomas (t = 4.57; P < .01). In addition, the methylation levels were associated closely with gender (t = 6.44; P < .001). CONCLUSIONS: The results indicated that tumor tissues from patients with osteosarcoma had a significantly higher incidence of hypermethylation for several genes compared with corresponding normal tissues. The epigenetic changes observed in this study may have prognostic importance for patients with osteosarcoma.

Adolescent↗
PubMed2006

Integrated molecular profiling of SOD2 expression in multiple myeloma.

Reactive oxygen species are known to be involved in several cellular processes, including cell signaling. SOD2 is a key enzyme in the conversion of reactive oxygen species and has been implicated in a host of disease states, including cancer. Using an integrated, whole-cell approach encompassing epigenetics, genomics, and proteomics, we have defined the role of SOD2 in multiple myeloma. We show that the SOD2 promoter is methylated in several cell lines and there is a correlative decrease in expression. Furthermore, myeloma patient samples have decreased SOD2 expression compared with healthy donors. Overexpression of SOD2 results in decreased proliferation and altered sensitivity to 2-methoxyestradiol-induced DNA damage and apoptosis. Genomic profiling revealed regulation of 65 genes, including genes involved in tumorigenesis, and proteomic analysis identified activation of the JAK/STAT pathway. Analysis of nearly 400 activated transcription factors identified 31 transcription factors with altered DNA binding activity, including XBP1, NFAT, forkhead, and GAS binding sites. Integration of data from our gestalt molecular analysis has defined a role for SOD2 in cellular proliferation, JAK/STAT signaling, and regulation of several transcription factors.

2-Methoxyestradiol↗
PubMed2004

Hypermethylation of the GATA genes in lung cancer.

PURPOSE: In lung cancer, DNA hypermethylation is known to be a common event. EXPERIMENTAL DESIGN: Gene expression and methylation status of GATA-4, GATA-5, and GATA-6 were analyzed with cell lines and primary human lung cancers. Methylation profiles of primary lung cancers were analyzed and correlated with clinical as well as histopathological data. RESULTS: Complete methylation was detected by methylation-specific PCR for both GATA-4 and GATA-5 in four cell lines (H358, DMS-53, A549, and H1299), all of which had no expression by reverse transcription-PCR analysis. Demethylation with 5-aza-2'deoxycytidine restored expression in each case. GATA-6 was ubiquitously expressed in all of the six cell lines. GATA-4 bisulfite sequencing revealed complete methylation of the GATA-4 promoter in H358 cells, correlating well with its lack of expression at the mRNA level. Only a few CpG sites showed methylation by bisulfite sequencing within the GATA-4 promoter in a cell line that expressed the gene. In 63 cases of primary lung cancers, GATA-4 and GATA-5 promoter methylation was detected in (42 of 63) 67% and (26 of 63) 41%, respectively. GATA-6 remained unmethylated both in cell lines and primary tumors. Six autopsy specimens of normal lung tissue showed no aberrant promoter hypermethylation for the GATA genes. Correlation of concomitant GATA-4 and GATA-5 methylation with clinicopathological parameters only found a statistically significant increase in methylation frequency with increasing patient age (P < 0.001). CONCLUSIONS: These epigenetic changes in the GATA genes in lung cancer are tumor-specific, relate to the loss of GATA gene expression, and occur increasingly in the elderly.

Adenocarcinoma↗