Abstract
To identify novel methylation-silenced genes in gastric cancer, we carried out a genome-wide
search for genes that are up-regulated after treatment with the demethylating agent,
5-aza-2′-deoxycytidine (5Aza-dC). When three gastric cancer cell lines (SNU-1,-601,
and -719) were treated with 5Aza-dC, 143 genes were found to be upregulated by twofold
or more using oligonucleotide microarrays. Six of these genes, i.e. TFPI2, GPX3, GPX1, IGFBP6, IRF7 and DMRT1, showed promoter hypermethylation in one or more gastric cancer cell lines, but were
unmethylated in normal gastric mucosa by bisulphite sequencing and methylation-specific
PCR analysis. The following percentages of these genes were found to be aberrantly
methylated in gastric cancer samples; TFPI2 (80.9%), GPX3 (30.1%), DMRT1 (46.9%), GPX1 (16.7%), IGFBP6 (22.6%) and IRF7 (32.1%). Interestingly, the survival of patients possessing methylated alleles of
TFPI2 (123/152, 80.9%) was poorer than that of patients with unmethylated alleles (p = 0.023). Multivariate analysis confirmed that TFPI2 methylation is a significant and independent prognostic factor in gastric carcinoma.
Furthermore, altered TFPI2 expression, as demonstrated by immunohistochemistry in 566 consecutive gastric cancer
tissues, was found to be significantly associated with sex (p = 0.003), WHO classification (p < 0.001), and a mixed subtype by Lauren’s classification (p < 0.001). Thus, the present study identified several novel genes, which were methylated
in gastric cancer and among them, methylation of TFPI2 was an unfavourable prognostic marker.
Keywords
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References
- Global cancer statistics, 2002.CA Cancer J Clin. 2005; 55: 74-108
- The fundamental role of epigenetic events in cancer.Nat Rev Genet. 2002; 3: 415-428
- Focus on gastric cancer.Cancer Cell. 2004; 5: 121-125
- Alterations in DNA methylation: a fundamental aspect of neoplasia.Adv Cancer Res. 1998; 72: 141-196
- Cancer epigenetics comes of age.Nat Genet. 1999; 21: 163-167
- 5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers.Nat Med. 1995; 1: 686-692
- Detection and interpretation of altered methylation patterns in cancer cells.Nat Rev Cancer. 2005; 5: 223-231
- Emerging molecular markers of cancer.Nat Rev Cancer. 2002; 2: 210-219
- CpG island methylation in premalignant stages of gastric carcinoma.Cancer Res. 2001; 61: 2847-2851
- Profile of aberrant CpG island methylation along the multistep pathway of gastric carcinogenesis.Lab Invest. 2003; 83: 635-641
- Frequent CpG island methylation in precursor lesions and early gastric adenocarcinomas.Oncogene. 2004; 23: 4646-4654
- Epigenetic inactivation of CHFR and sensitivity to microtubule inhibitor in gastric cancer.Cancer Res. 2003; 63: 8606-8613
- E-Cadherin gene promoter hypermethylation in primary human gastric carcinomas.J Natl Cancer Inst. 2000; 92: 569-573
- Promoter hypermethylation of tumor-related genes in gastric intestinal metaplasia of patients with and without gastric cancer.Int J Cancer. 2002; 102: 623-628
- Histone deacetylases and cancer: causes and therapies.Nat Rev Cancer. 2001; 1: 194-202
- Histone acetylation/deacetylation and cancer: an “open” and “shut” case?.Curr Mol Med. 2001; 1: 401-429
- Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex.Nature. 1998; 393: 386-389
- DNMT1 binds HDAC2 and a new co-repressor, DMAP-1, to form a complex at replication foci.Nat Genet. 2000; 25: 269-277
- Trichostatin and leptomycin. Inhibition of histone deacetylation and signal-dependent nuclear export.Ann NY Acad Sci. 1999; 886: 23-36
- Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer.Nat Genet. 1999; 21: 103-107
- A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer.Nat Genet. 2002; 31: 141-149
- The power and the promise of DNA methylation markers.Nat Rev Cancer. 2003; 3: 253-266
- Discovery of novel targets for aberrant methylation in pancreatic carcinoma using high-throughput microarrays.Cancer Res. 2003; 63: 3735-3742
- Protein expression profiling and molecular classification of gastric cancer by the tissue array method.Clin Cancer Res. 2007; 13: 4154-4163
- Loss of caspase-1 gene expression in human gastric carcinomas and cell lines.Int J Oncol. 2005; 26: 1265-1271
- Tumour suppressor gene expression correlates with gastric cancer prognosis.J Pathol. 2003; 200: 39-46
- Pharmacologic unmasking of epigenetically silenced tumor suppressor genes in esophageal squamous cell carcinoma.Cancer Cell. 2002; 2: 485-495
- Excessive CpG island hypermethylation in cancer cell lines versus primary human malignancies.Hum Mol Genet. 2001; 10: 1413-1419
- The emerging science of epigenomics.Hum Mol Genet. 2006; 15: R95-R101
- AKAP12/Gravin is inactivated by epigenetic mechanism in human gastric carcinoma and shows growth suppressor activity.Oncogene. 2004; 23: 7095-7103
- Downregulation of ID4 by promoter hypermethylation in gastric adenocarcinoma.Oncogene. 2003; 22: 6946-6953
- Mechanism for inactivation of the KIP family cyclin-dependent kinase inhibitor genes in gastric cancer cells.Cancer Res. 2000; 60: 262-265
- Inactivation of the 14–3–3 sigma gene is associated with 5′ CpC island hypermethylation in human cancers.Cancer Res. 2000; 60: 4353-4357
- Profile of aberrant CpG island methylation along multistep gastric carcinogenesis.Lab Invest. 2003; 83: 519-526
- Glutathion peroxidase 3, deleted or methylated in prostate cancer, suppresses prostate cancer growth and metastasis.Cancer Res. 2007; 67: 8043-8050
- Hypermethylation and loss of expression of glutathione peroxidase-3 in Barrett’s tumorigenesis.Neoplasia. 2005; 7: 854-861
- Discovery of novel methylation biomarkers in cervical carcinoma by global demethylation and microarray analysis.Cancer Epidemiol Biomarkers Prev. 2006; 15: 114-123
- Epigenetic inactivation of TFPI-2 as a common mechanism associated with growth and invasion of pancreatic ductal adenocarcinoma.Oncogene. 2005; 24: 850-858
- Expression and methylation status of tissue factor pathway inhibitor-2 gene in non-small-cell lung cancer.Br J cancer. 2005; 92: 775-783
- Microarray analysis of promoter methylation in lung cancers.J Hum Genet. 2006; 51: 368-374
- Methylation profiling of twenty four genes and the concordant methylation behaviours of nineteen genes that may contribute to hepatocellular carcinogenesis.Cell Res. 2003; 13: 319-333
- Modulation by decitabine of gene expression and growth of osteosarcoma U2OS cells in vitro and xenografts: Identification of apoptotic genes as targets for demethylation.Cancer Cell Int. 2007; 7: 14
- Novel extracellular matrix associated serine proteinase inhibitors from human skin fibroblasts.Arch Biochem Biophys. 1995; 317: 311-314
- Hypermethylation of O6-methylguanine-DNA methyltransferase promoter may predict nonrecurrence after chemotherapy in colorectal cancer cases.Clin Cancer Res. 2003; 9: 5306-5312
Article info
Publication history
Published online: February 05, 2009
Accepted:
December 19,
2008
Received in revised form:
December 17,
2008
Received:
August 21,
2008
Identification
Copyright
© 2008 Elsevier Ltd. Published by Elsevier Inc. All rights reserved.
