Abstract
Background: DNA methylation represents one of the most common epigenetic changes in human cancer providing important information regarding carcinogenesis. A possible role as a prognostic indicator has also been proposed. The aim of our study was to evaluate the prognostic significance of SOX17 promoter methylation status in patients with operable gastric cancer.
Methods: Using methylation-specific PCR (MSP) we examined the incidence and prognostic significance of SOX17 methylation status in cell free circulating DNA in the serum of 73 patients with operable gastric cancer. Fifty-one patients were male (69.9%), their median age was 65 years, 43 patients (58.9%) had regional lymph node involvement and all had a Performance Status (WHO) of 0–1.
Results: SOX17 promoter was found to be methylated in 43 out of 73 gastric cancer serum samples examined (58.9%). All 20 control serum samples from healthy individuals were negative. Overall survival (OS) was found to be significantly associated with SOX17 methylation (p=0.049). A significant correlation between methylation status and differentiation (p=0.031) was also observed. No other significant associations between different tumor parameters examined and SOX17 methylation status were observed.
Conclusions: SOX17 promoter methylation in cell free DNA of patients with operable gastric cancer is a frequent event and may provide important information regarding prognosis in this group of patients.
Conflict of interest statement
Authors’ conflict of interest disclosure: The authors stated that there are no conflicts of interest regarding the publication of this article.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
References
1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics 2002. CA Cancer J Clin 2005;55:74–108.10.3322/canjclin.55.2.74Search in Google Scholar PubMed
2. Hayatt BG, Paull PE, Wassef W. Gastric oncology: an update. Curr Opin Gastroenterol 2009;25:570–8.10.1097/MOG.0b013e328331b5c9Search in Google Scholar PubMed
3. Callinan PA, Feinberg AP. The emerging science of epigenomics. Hum Mol Genet 2006;15:95–101.10.1093/hmg/ddl095Search in Google Scholar PubMed
4. Laird PW. The power and promise of DNA methylation markers. Nat Rev Cancer 2003;3:253–66.10.1038/nrc1045Search in Google Scholar PubMed
5. Bird A. DNA methylation patterns and epigenetic memory. Genes Dev 2002;16:6–21.10.1101/gad.947102Search in Google Scholar PubMed
6. Kopelovich L, Crowell JA, Fay JR. The epigenome as a target for cancer chemoprevention. J Natl Cancer Inst 2003;95:1747–57.10.1093/jnci/dig109Search in Google Scholar PubMed
7. Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 2003;349: 2042–54.10.1056/NEJMra023075Search in Google Scholar PubMed
8. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet 2002;3:415–28.10.1038/nrg816Search in Google Scholar PubMed
9. Dammann R, Yang G, Pfeifer GP. Hypermethylation of the CpG island of Ras association domain family 1A (RASSF1A), a putative tumor suppressor gene from the 3p21.3 locus, occurs in a large percentage of human breast cancers. Cancer Res 2001;61:3105–9.Search in Google Scholar
10. Fackler MJ, McVeigh M, Evron E, Garrett E, Mehrotra J, Polyak K, et al. DNA methylation of RASSF1A, HIN-1, RAR-beta, Cyclin D2 and Twist in in situ and invasive lobular breast carcinoma. Int J Cancer 2003;107:970–5.10.1002/ijc.11508Search in Google Scholar PubMed
11. Balassiano K, Lima S, Jenab M, Overvad K, Tjonneland A, Boutron-Riault MC. Aberrant DNA methylation of cancer associated genes in gastric cancer in the European Prospective Investigation into cancer and Nutrition (EPIC-EURGAST). Cancer Lett 2011;311:85–95.10.1016/j.canlet.2011.06.038Search in Google Scholar PubMed
12. Fleisher AS, Esteller M, Wang S, Tamura G, Suzuki H, Yin J, et al. Hypermethylation of the hMLH1 gene promoter in human gastric cancers with microsatellite instability. Cancer Res 1999;59:1090–5.Search in Google Scholar
13. Ibanez de Caceres I, Battagli C, Esteller M, Herman JG. Tumor cell-specific BRCA1 and RASSF1A hypermethylation in serum, plasma and peritoneal fluid from ovarian cancer patients. Cancer Res 2004;64:6476–81.10.1158/0008-5472.CAN-04-1529Search in Google Scholar
14. Palmisiano WA. Predicting lung cancer by detecting aberrant promote methylation in sputum. Cancer Res 2000;60:5954–8.Search in Google Scholar
15. Goessl C, Muller M, Straub B, Muller K. DNA alterations in body fluids as molecular tumor markers for urological malignancies. Eur Urol 2002;41:668–76.10.1016/S0302-2838(02)00126-4Search in Google Scholar
16. Oishi Y, Watanabe Y, Yoshida Y, Sato Y. Hypermethylation of SOX17 gene is useful as a molecular diagnostic application in early gastric cancer. Tumour Biol 2012;33:383–93.10.1007/s13277-011-0278-ySearch in Google Scholar PubMed
17. Swarup V, Rajeswari MR. Circulating (cell-free) nucleic acids – A promising non-invasive tool for early detection of several human diseases. FEBS Lett 2007;581:795–9.10.1016/j.febslet.2007.01.051Search in Google Scholar PubMed
18. Mori T, O’Day SJ, Umetani N. Predictive utility of circulating methylated DNA in serum of melanoma patients receiving biochemotherapy. J Clin Oncol 2005;23:9351–8.10.1200/JCO.2005.02.9876Search in Google Scholar PubMed PubMed Central
19. Goebel G, Zitt M, Muller HM. Circulating nucleic acids in plasma or serum (CNAPS) as prognostic and predictive markers in patients with solid neoplasias. Dis Markers 2005;21:105–20.10.1155/2005/218759Search in Google Scholar PubMed PubMed Central
20. Fu DY, Wang ZM, Chen L, Wang BL, Shen ZZ, Huang W, et al. SOX17, the canonical Wnt antagonist, is epigenetically inactivated by promoter methylation in human breast cancer. Breast Cancer Res Tr 2010;119:601–12.10.1007/s10549-009-0339-8Search in Google Scholar PubMed
21. Sohn J, Natale J, Chew LJ, Belachew S, Cheng Y, Aguirre A, et al. Identification of SOX17 as a transcription factor that regulates oligodendrocyte development. J Neurosci 2006;26:9722–35.10.1523/JNEUROSCI.1716-06.2006Search in Google Scholar PubMed PubMed Central
22. Matsui T, Kanai-Azuma M, Hara K, Matoba S, Hiramatsu R, Kawakami H, et al. Redundant roles of Sox17 and Sox18 in postnatal angiogenesis in mice. J Cell Sci 2006;119: 3513–26.10.1242/jcs.03081Search in Google Scholar PubMed
23. Park KS, Wells JM, Zorn AM, Wert SE, Whitsett JA. Sox17 influences the differentiation of respiratory epithelial cells. Dev Biol 2006;294:192–202.10.1016/j.ydbio.2006.02.038Search in Google Scholar PubMed
24. Sinner D, Kordich JJ, Spence JR, Opoca R, Rankin S, Lin SC, et al. Sox17 and Sox4 differentially regulate beta-catenin/T-cell factor activity and proliferation of colon carcinoma cells. Mol Cell Biol 2007;27:7802–15.10.1128/MCB.02179-06Search in Google Scholar
25. Zhang W, Glöckner SC, Guo M, Machida EO, Wang DH, Easwaran H, et al. Epigenetic inactivation of the canonical Wnt antagonist SRY-box containing gene 17 in colorectal cancer. Cancer Res 2008;68:2764–72.10.1158/0008-5472.CAN-07-6349Search in Google Scholar
26. Du YC, Oshima H, Oguma K, Kitamura T, Itadani H, Fujimura T, et al. Induction and down regulation of SOX17 and its possible roles during the course of gastrointestinal tumorigenesis. Gastroenterology 2009;137:1346–57.10.1053/j.gastro.2009.06.041Search in Google Scholar
27. Knudson AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971;68:820–3.10.1073/pnas.68.4.820Search in Google Scholar
28. Korinek V, Barker N, Moerer P, van Donselaar E, Huls G, Peters PJ, et al. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet 1998;19: 379–83.10.1038/1270Search in Google Scholar
29. Van de Wetering M, Sancho E, Verweij C, de Lau W, Oving I, Hurlstone A, et al. The β-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 2002;111:241–50.10.1016/S0092-8674(02)01014-0Search in Google Scholar
30. Clements WM, Wang J, Sarnaik A, Kim OJ, MacDonald J, Fenoglio-Preiser C, et al. Beta-Catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Cancer Res 2002;62:3503–6.Search in Google Scholar
31. Fodde R, Smits R, Clevers H. APC signal transduction and genetic instability in colorectal cancer. Nat Rev Cancer 2001;1:55–67.10.1038/35094067Search in Google Scholar PubMed
32. Fodde R, Brabletz T. Wnt/β-Catenin signaling in cancer stemness and malignant behavior. Curr Opin Cell Biol 2007;19: 150–8.10.1016/j.ceb.2007.02.007Search in Google Scholar PubMed
©2013 by Walter de Gruyter Berlin Boston
