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Updated: Sep 23, 2026
Genome-Wide Analysis of DNA Methylation in Gastrointestinal Cancer
Published on: September 18, 2020
Discovery of novel targets for aberrant methylation in pancreatic carcinoma using high-throughput microarrays
Norihiro Sato1, Noriyoshi Fukushima, Anirban Maitra
1Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205-2196, USA.
Abstract:
To identify potential targets for aberrant methylation in pancreatic cancer, we analyzed global changes in gene expression profiles of four pancreatic cancer cell lines after treatment with the demethylating agent 5-aza-2'-deoxycytidine (5Aza-dC) and/or the histone deacetylase inhibitor trichostatin A. A substantial number of genes were induced 5-fold or greater by 5Aza-dC alone (631 transcripts), trichostatin A alone (1196 transcripts), and by treatment with both agents (857 transcripts). Four hundred and seventy-five genes were markedly (>5-fold) induced after 5Aza-dC treatment in pancreatic cancer cell lines but not in a nonneoplastic pancreatic epithelial cell line. The methylation status of 11 of these 475 genes was examined in a panel of 42 pancreatic cancers, and all 11 of these genes were aberrantly methylated in pancreatic cancer but rarely, if any, methylated in 10 normal pancreatic ductal epithelia. These genes include UCHL1 (methylated in 100% of 42 pancreatic cancers), NPTX2 (98%), SARP2 (95%), CLDN5 (93%), reprimo (86%), LHX1 (76%), WNT7A (71%), FOXE1 (69%), TJP2 (64%), CDH3 (19%), and ST14 (10%). Three of these 11 genes (NPTX2, SARP2, and CLDN5) were selected for further analysis in a larger panel of specimens, and aberrant methylation of at least one of these three genes was detectable in 100% of 43 primary pancreatic cancers and in 18 of 24 (75%) pancreatic juice samples obtained from patients with pancreatic cancer. Thus, a substantial number of genes are induced by 5Aza-dC treatment of pancreatic cancer cells, and many of them may represent novel targets for aberrant methylation in pancreatic carcinoma.
Insights
Researchers identified novel gene targets for aberrant methylation in pancreatic cancer. Treatment with 5-aza-2'-deoxycytidine (5Aza-dC) and trichostatin A induced numerous genes, with 11 found to be aberrantly methylated in pancreatic tumors.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Pancreatic cancer is a deadly disease with limited therapeutic options.
- Aberrant gene methylation is a hallmark of cancer, driving tumor development.
- Identifying novel methylation targets is crucial for developing new diagnostic and therapeutic strategies.
Purpose of the Study:
- To identify novel genes with aberrant methylation in pancreatic cancer.
- To investigate the effect of demethylating agents on gene expression in pancreatic cancer cells.
- To validate potential methylation targets in clinical samples.
Main Methods:
- Global gene expression profiling of pancreatic cancer cell lines treated with 5-aza-2 '-deoxycytidine (5Aza-dC) and/or trichostatin A.
- Analysis of gene induction (>5-fold) by drug treatment.
- Methylation-specific analysis of candidate genes in pancreatic cancer tissues and normal epithelia.
- Validation of aberrant methylation in primary tumors and pancreatic juice samples.
Main Results:
- Treatment with 5Aza-dC and/or trichostatin A induced a substantial number of genes.
- 475 genes were significantly induced by 5Aza-dC in cancer cells but not normal cells.
- 11 of these genes showed aberrant methylation in 42 pancreatic cancers, including UCHL1 (100%), NPTX2 (98%), and SARP2 (95%).
- Aberrant methylation of NPTX2, SARP2, and CLDN5 was detected in 100% of 43 primary pancreatic cancers and 75% of pancreatic juice samples.
Conclusions:
- A significant number of genes are epigenetically regulated in pancreatic cancer.
- Several novel genes, including UCHL1, NPTX2, and SARP2, are frequently aberrantly methylated in pancreatic cancer.
- These aberrantly methylated genes represent promising novel targets for pancreatic cancer diagnosis and therapy.
