Ann Surg Oncol (2009) 16:2077–2078 DOI 10.1245/s10434-009-0472-y
LETTER TO THE EDITOR
Epigenetics in Gastric Cancer: Challenges for Clinical Implications
TO THE EDITORS: Classic genetics alone cannot explain sporadic cancer and cancer development in patients with weak family history. The concept of epigenetics offers a partial explanation and may have important clinical implications for these types of cancer. The best-known epigenetic marker is DNA methylation, which occurs in CpG sites (islands), has critical roles in the control of gene activity, and is influenced by the modifications in histone structure that are commonly disrupted in cancer cells.1 Hypermethylation of the CpG islands in the promoter regions of tumor-suppressor genes is a major event in the origin of many cancers. It can affect genes involved in the cell cycle, DNA repair, the metabolism of carcinogens, cell-to-cell interaction, apoptosis, and angiogenesis, all of which are involved in the development of cancer.1 Hypermethylation occurs at different stages in the development of cancer and in different cellular networks, and it interacts with genetic lesions. Such interactions can be seen when hypermethylation inactivates the CpG island of the promoter of the DNA-repair genes hMLH1 (colon, stomach cancer), BRCA1 (breast cancer), and other genes.2,3 In each case, silencing of the DNA-repair gene blocks the repair of genetic mistakes, thereby opening the way to neoplastic transformation of the cell. The profiles of hypermethylation of the CpG islands in tumor-suppressor genes are specific to the cancer type.1 Each tumor type, including gastric cancer, can be assigned a specific, defining DNA ‘‘hypermethylome.’’ Such patterns of epigenetic inactivation occur not only in sporadic tumors but also in inherited cancer syndromes.3 The DNA-methylation and histone-modification patterns associated with the development and progression of cancer have potential clinical use. DNA hypermethylation markers are under study as complementary diagnostic tools, prognostic factors, and predictors of responses to treatment in many cancer types, including breast cancer. DNA methylation techniques permit the sensitive and quantitative detection of hypermethylated tumor-suppressor genes in
all types of biologic fluids and biopsy specimens. The establishment of DNA-methylation and histone-modification profiles of the primary tumor specimen itself might be a valuable tool in determining the prognosis and predicting the patient’s response to therapies. Prognostic dendrograms similar to those used in gene-expression microarray analyses, with the use of a combination of hypermethylated markers and CpG-island microarrays, have been developed. These epigenomic profiles are complementary to profiles of gene-expression patterns and can be developed with DNA extracted from archived material.1 Overall, prognosis of gastric cancer, particularly in the Western world, is poor. Prognostic and predictive biomarkers are urgently needed for a gastric cancer patienttailored treatment. Microarray technology provides fascinating opportunities for the development of markers. Novel comprehensive models for personalized treatment are proposed using gene expression profiling data.4 Park and colleagues in the July issue of the Journal, report on histone modification pattern in gastric cancer.5 The authors used immunohistochemistry to evaluate the patterns of histone H3 and H4 acetylation and trimethylation in gastric cancer samples. Double 2-mm core tissue microarrays were made from 261 paraffin-embedded gastric adenocarcinoma samples in stomach cancers. Park et al. found that trimethylation of H3K9 was positively correlated with tumor stage (P = 0.043) and cancer recurrence (P = 0.043). Higher level of H3K9 trimethylation was associated with a poor survival rate (P = 0.008). On multivariate survival analysis, H3K9 trimethylation status was an independent prognostic factor (P = 0.014). Methylation dominance was also an independent prognostic factor (P = 0.026) in multivariate survival analysis. The authors conclude that the pattern of histone modification may be useful as a predictor for gastric cancer recurrence. More recently, the discovery of inactivation of microRNA (miRNA) genes by DNA methylation may also have clinical utility. Short, 22-nucleotide, noncoding RNAs that regulate gene expression are called miRNAs. DNA hypermethylation in the miRNA 5’ regulatory region is a mechanism that can account for the downregulation of miRNA in tumors.6,7 The methylation silencing of miR-124a also causes activation of the cyclin D–kinase 6 oncogene (CDK6), and it is a common epigenetic lesion in tumors.7 Research on genetics, epigenetics, and most recently personal genomics provides already exciting findings toward the discovery of markers to predict a person’s risk
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for cancer or a patient’s risk for recurrence.8–11 Currently, the advent of next-generation DNA sequencing technology makes feasible cheaper and faster whole-genome sequencing allowing the unbiased discovery of candidate genes and risk variants such as single-nucleotide polymorphisms and copy-number variants that maybe relevant for cancer. Novel cancer-initiating and cancer-metastasis mutations may be used as both response predictors and targets for anticancer therapeutics.12–14 D. Ziogas, MD, and D. Roukos, MD Department of Surgery, Ioannina University School of Medicine, Ionnina, Greece e-mail:
[email protected] Published Online: 2 May 2009 Ó Society of Surgical Oncology 2009
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D. Ziogas, D. Roukos 4. Roukos DH. Innovative genomic-based model for personalized treatment of gastric cancer: integrating current standards and new technologies. Expert Rev Mol Diagn. 2008;8(1):29–39. 5. Park YS, Jin MY, Kim YJ, Yook JH, Kim BS, Jang SJ. The global histone modification pattern correlates with cancer recurrence and overall survival in gastric adenocarcinoma. Ann Surg Oncol. 2008;15(7):1968–76. 6. Saito Y, Liang G, Egger G, et al. Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell. 2006;9:435–43. 7. Lujambio A, Ropero S, Ballestar E, et al. Genetic unmasking of an epigenetically silenced microRNA in human cancer cells. Cancer Res. 2007;67:1424–9 (Erratum). 8. Manolio TA, Brooks LD, Collins FS. A HapMap harvest of insights into the genetics of common disease. J Clin Invest. 2008; 118:1590–605. 9. Roukos DH. Genetics and genome-wide association studies: surgery-guided algorithm and promise for future breast cancer personalized surgery. Expert Rev Mol Diagn. 2008;8(5):587–97. 10. Roukos DH. 21-gene assay: Challenges and promises in translating personal genomics and whole genome scans into personalized treatment of breast cancer. J Clin Oncol. 2009;27(8):1337–8. 11. Roukos DH, Lykoudis E, Liakakos T. Genomics and challenges toward personalized breast cancer local control. J Clin Oncol. 2008; 26(26):4360-1. 12. My genome. So, what? Nature. 2008;456(7218):1 (editorial). 13. Ley TJ, Mardis ER, Ding L, et al. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature. 2008;456(7218):66–72. 14. Roukos DH. Assessing genetic variations—SNPs/CNVs—and interactions with environment for personalized gastric cancer prevention: Can personal genomics challenges be overcome? Expert Rev Mol Diagn. 2009;9(1):1–6.
