DOI: http://dx.doi.org/10.18203/2320-6012.ijrms20161783

Hypermethylation of tumor suppressor genes in gastric cancer: associations with demographic and clinicopathological characteristics

Binnur Bagci, Kursat Karadayi, Gokhan Bagci, Hatice Ozer, Ersin Tuncer, Ilhan Sezgin, Mustafa Turan

Abstract


Background: Gastric cancer (GC) is one of the most common cancers worldwide. Despite the declining prevalence in Western countries, it is still a major health problem in Turkey and Asian countries. In the current study, we investigated the hypermethylation status of 25 TSGs in GC. Furthermore, the association between hypermethylation status of these TSGs and some demographic and clinicopathological characteristics were investigated.

Methods: Formalin-fixed paraffin-embedded tissue samples obtained from 27 patients with GC and genomic DNA isolated from these tissues. To compare the methylation status of 25 TSGs, methylation-specific multiplex ligation-dependent probe amplification (MS–MLPA) technique was used. Results were evaluated in terms of age, gender, positive lymph node status, lymphovascular invasion, perineural invasion, mortality and five-years of survival, retrospectively.

Results: Tumor suppressor gene hypermethylation was detected 16 (59.3%) of 27 GC tissues. Patients with hypermethylation-detected and patients with no hypermethylation-detected in their TSGs were classified as group 1 and group 2, respectively. The mean age of group 1 was 66.38±7.43 and the mean age of group 2 was found as 58.18±11.12 (p= 0.03). Hypermethylation was detected in 12 of 25 TSGs in patients with GC. Hypermethylation was detected as 51.8% for WT1, 40.7% for ESR1, 18.5% for CDH13, 14.8% for MSH6 and CD44, 7.4% for TP73 and PAX5 genes in the tumor tissues of patients with GC. Mean positive lymph node number was 8.81±5.38 in group 1 and 4.81±3.21 in group 2 (p= 0.037). Lymphovascular invasion, perineural invasion, mortality and five-years of mean survival were not statistically different between group 1 and group 2 (p>0.05 for all comparisons).

Conclusions: Hypermethylation frequency of certain tumor suppressor genes may increase with advancing age and with positive lymph nodes in gastric cancer patients.

 


Keywords


Gastric cancer, Tumor suppressor gene, Hypermethylation, WT1, ESR1

Full Text:

PDF

References


Yalcin S. Gastric cancer in Turkey-a bridge between west and east. Gastrointest Cancer Res. 2009;3:29-32.

Tan IB, Ng I, Tai WM, Tan P. Understanding the genetic basis of gastric cancer: recent advances. Expert Rev Gastroenterol. Hepatol. 2012;6:335-41.

Resende C, Ristimäki A, Machado JC. Genetic and epigenetic alteration in gastric carcinogenesis. Helicobacter. 2010;15(Suppl 1):34-9.

Crew KD, Neugut AI. Epidemiology of gastric cancer. World J Gastroenterol. 2006;12:354-62.

Herceg Z, Hainaut P. Genetic and epigenetic alterations as biomarkers for cancer detection, diagnosis and prognosis. Mol Oncol. 2007;1:26-41.

Burgio E, Migliore L. Towards a systemic paradigm in carcinogenesis: linking epigenetics and genetics. Mol Biol Rep. 2014;42:777-90.

Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128:683-92.

You JS, Jones PA. Cancer genetics and epigenetics: two sides of the same coin? Cancer cell. 2012;22:9-20.

Jones PA, Laird PW. Cancer-epigenetics comes of age. Nat Genet. 1999;21:163-7.

Esteller M. CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene. 2002;21:5427-40

Kang GH, Shim YH, Jung HY, Kim WH, Ro JY, Rhyu MG. CpG island methylation in premalignant stages of gastric carcinoma. Cancer Res. 2001;61:2847-51.

Zitt M, Zitt M, Müller HM. DNA methylation in colorectal cancer–impact on screening and therapy monitoring modalities?. Dis Markers. 2007;23:51-71.

Kondo Y, Issa JP. Epigenetic changes in colorectal cancer. Cancer Metastasis Rev. 2004;23:29-39.

In-Seon CHOI, Tsung-Teh WU. Epigenetic alterations in gastric carcinogenesis. Cell Res. 2005;15:247-54.

Kang GH, Lee HJ, Hwang KS, Lee S, Kim JH, Kim JS. Aberrant CpG island hypermethylation of chronic gastritis, in relation to aging, gender, intestinal metaplasia, and chronic inflammation. Am J Pathol. 2003;163:1551-6.

Moelans CB, Verschuur-Maes AH, van Diest PJ. Frequent promoter hypermethylation of BRCA2, CDH13, MSH6, PAX5, PAX6 and WT1 in ductal carcinoma in situ and invasive breast cancer. J Pathol. 2011;225:222-31.

Jung EJ, Kim IS, Lee EY, Kang JE, Lee SM, Kim DC et al. Comparison of methylation profiling in cancerous and their corresponding normal tissues from korean patients with breast cancer. Ann Lab Med. 2013;33:431-40.

Joensuu EI, Abdel-Rahman WM, Ollikainen M, Ruosaari S, Knuutila S, Peltomäki P. Epigenetic signatures of familial cancer are characteristic of tumor type and family category. Cancer Res. 2008;68:4597-605.

Gylling A, Abdel-Rahman WM, Juhola M, Nuorva K, Hautala E, Järvinen HJ et al. Is gastric cancer part of the tumour spectrum of hereditary non-polyposis colorectal cancer? A molecular genetic study. Gut. 2007;56:926-33.

Rengucci C, De Maio G, Casadei Gardini A, Zucca M, Scarpi E, Zingaretti C et al. Promoter methylation of tumor suppressor genes in pre-neoplastic lesions; potential marker of disease recurrence. J Exp Clin Cancer Res. 2014;33:65.

Englert C, Hou X, Maheswaran S, Bennett P, Ngwu C, Re GG et al. WT1 suppresses synthesis of the epidermal growth factor receptor and induces apoptosis. EMBO J. 1995;19:4662-75.

Zheng Y, Chen L, Li J, Yu B, Su L, Chen X et al. Hypermethylated DNA as potential biomarkers for gastric cancer diagnosis. Clin Biochem. 2011;18:1405-11.

Dahlman-Wright K, Cavailles V, Fuqua SA, Jordan VC, Katzenellenbogen JA, Korach KS et al. International Union of Pharmacology. LXIV. Estrogen receptors. Pharmacol Rev. 2006;58:773-81.

Woo IS, Park MJ, Choi SW, Kim SJ, Lee MA, Kang JH et al. Loss of estrogen receptor-alpha expression is associated with hypermethylation near its ATG start codon in gastric cancer cell lines. Oncol Rep. 2004;11:617-22.

Takeuchi T, Ohtsuki Y. Recent progress in T-cadherin (CDH13, H-cadherin) research. Histol Histopathol. 2001;16:1287-93.

Yan Q, Zhang ZF, Chen XP, Gutmann DH, Xiong M, Xiao ZY et al. Reduced T-cadherin expression and promoter methylation are associated with the development and progression of hepatocellular carcinoma. Int J Oncol. 2008;32:1057-63.

Tang Y, Dai Y, Huo J. Decreased expression of T-cadherin is associated with gastric cancer prognosis. Hepatogastroenterology. 2012;59:1294-8.

Hibi K, Kodera Y, Ito K, Akiyama S, Nakao A. Methylation pattern of CDH13 gene in digestive tract cancers. Br J Cancer. 2004;91:1139-42.

Martik D, Baitinger C, Modrich P. Differential specificities and simultaneous occupancy of human MutSα nucleotide binding sites. J Biol Chem. 2004;279:28402-10.

Montgomery E, Abraham SC, Fisher C, Deasel MR, Amr SS, Sheikh SS et al. CD44 loss in gastric stromal tumors as a prognostic marker. Am J Surg Pathol. 2004;28:168-77.

Goodison S, Urquidi V, Tarin D. CD44 cell adhesion molecules. Mol Pathol. 1999;52:189-96.

Cobaleda C, Schebesta A, Delogu A, Busslinger M. Pax5: the guardian of B cell identity and function. Nat Immunol. 2007;8:463-70.

Adams B, Dorfler P, Aguzzi A, Kozmik Z, Urbánek P, Maurer-Fogy I et al. Pax-5 encodes the transcription factor BSAP and is expressed in B lymphocytes, the developing CNS, and adult testis. Genes Dev. 1992;6:1589-607.

Li X, Cheung KF, Ma X, Tian L, Zhao J, Go MY et al. Epigenetic inactivation of paired box gene 5, a novel tumor suppressor gene, through direct upregulation of p53 is associated with prognosis in gastric cancer patients. Oncogene. 2012;31:3419-30.

Soldevilla B, Millán CS, Bonilla F, Domínguez G. The TP73 complex network: ready for clinical translation in cancer? Genes Chromosomes Cancer. 2013:52:989-1006.

Bernal C, Vargas M, Ossandón F, Santibáñez E, Urrutia J, Luengo V et al. DNA methylation profile in diffuse type gastric cancer: evidence for hypermethylation of the BRCA1 promoter region in early-onset gastric carcinogenesis. Biol Res. 2008;41:303-15.

Waki T, Tamura G, Sato M, Motoyama T. Age-related methylation of tumor suppressor and tumor-related genes: an analysis of autopsy samples. Oncogene. 2003;22:4128-4133.

Yao D, Shi J, Shi B, Wang N, Liu W, Zhang G et al. Quantitative assessment of gene methylation and their impact on clinical outcome in gastric cancer. Clinica Chimica Acta. 2012;413:787-94.

Wani M, Afroze D, Makhdoomi M, Hamid I, Wani B, Bhat G et al. Promoter methylation status of DNA repair gene (hMLH1) in gastric carcinoma patients of the Kashmir valley. Asian Pac J Cancer Prev. 2012;13:4177-81.

Hu SL, Kong XY, Cheng ZD, Sun YB, Shen G, Xu WP et al. Promoter methylation of p16, Runx3, DAPK and CHFR genes is frequent in gastric carcinoma. Tumori. 2010;96:726-33.