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The prognostic significance of p21 and Her-2 gene expression and mutation/polymorphism in patients with gastric adenocarcinoma

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Abstract

Analyses of gene expression status and genetic polymorphisms are methods to identify novel histopathological prognostic factors. In patients with gastric cancer, some cell cycle regulators p53, p21, p27 and Her-2 oncogene have been proposed as prognostic factors. We aimed to investigate the expression and mutation/polymorphism of p21 and Her-2 and also relationship between that genes status and histopathological factors and prognosis in patients with gastric cancer. Forty-four patients with locally advanced gastric cancer were analyzed in this study from January 2000 to December 2008. Clinicopathological parameters, expression and mutation/polymorphism of p21 and Her-2 results were used to predict disease-free survival and overall survival. The positive expression of p21 and Her-2 was observed in 61.4 % (n = 27) and 9.1 % (n = 4) of all 44 tumors, respectively. p21 gene mutation and Her-2 gene polymorphism were detected in 20 % (n = 11) and 2.3 % (n = 1, II phenotype) of cases, respectively. The negative expression of p21 was correlated significantly with diffuse and undifferential type histologies, whole gastric involvement and positive vascular/neural invasion. The median survival rate of patients with negative expression was significantly poorer than that of patients with positive expression of p21 (17 vs. 27 months, p = 0.01, cox regression). p21 mutation was significantly higher in patients with diffuse (p = 0.03) and undifferential (p = 0.02) type histologies. There was no statistically significant association between histopathological parameters and Her-2 gene polymorphism/expression. The negative expression of p21 correlates with disease survival and may be a poor prognostic factor in patients with resected gastric cancer treated with adjuvant chemotherapy.

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References

  1. Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, Haller DG, Ajani JA, Gunderson LL, Jessup JM, Martenson JA. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001;345:725–30.

    Article  PubMed  CAS  Google Scholar 

  2. Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol. 2008;19:1523–9.

    Article  PubMed  CAS  Google Scholar 

  3. Wagner AD, Moehler M. Development of targeted therapies in advanced gastric cancer: promising exploratory steps in a new era. Curr Opin Oncol. 2009;21:381–5.

    Article  PubMed  CAS  Google Scholar 

  4. Xiangming C, Hokita S, Natsugoe S, Tanabe G, Baba M, Takao S, Kuroshima K, Aikou T. p21 expression is a prognostic factor in patients with p53-negative gastric cancer. Cancer Lett. 2000;148:181–8.

    Article  PubMed  CAS  Google Scholar 

  5. Gamboa-Dominguez A, Seidl S, Reyes-Gutierrez E, Hermannstädter C, Quintanilla-Martinez L, Busch R, Höfler H, Fend F, Luber B. Prognostic significance of p21WAF1/CIP1, p27Kip1, p53 and E-cadherin expression in gastric cancer. J Clin Pathol. 2007;60:756–61.

    Article  PubMed  CAS  Google Scholar 

  6. Kouraklis G, Katsoulis IE, Theocharis S, Tsourouflis G, Xipolitas N, Glinavou A, Sioka C, Kostakis A. Does the expression of cyclin E, pRb, and p21 correlate with prognosis in gastric adenocarcinoma? Dig Dis Sci. 2009;54:1015–20.

    Article  PubMed  CAS  Google Scholar 

  7. El-Deiry WS, Harper JW, O’Connor PM, Velculescu VE, Canman CE, Jackman J, Pietenpol JA, Burrell M, Hill DE, Wang Y. WAF1/CIP1 is induced in p53 mediated G1 arrest and apoptosis. Cancer Res. 1994;54:1169–74.

    PubMed  CAS  Google Scholar 

  8. Sheikh MS, Rochefort H, Garcia M. Overexpression of p21/Waf1/Cip1 induced growth arrest, giant cell formation and apoptosis in human breast carcinoma cell lines. Oncogene. 1995;11:1487–98.

    Google Scholar 

  9. Chen CY, Faller DV. Direction of p21 generated signals towards cell growth or apoptosis is determined by protein kinase C and Bcl-2. Oncogene. 1995;11:1675–83.

    Google Scholar 

  10. Harper JW, Adami GR, Wei N, Keyomarsi K, Elledges SJ. The p21 Cdk-interacting protein Cip 1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 1993;75:805–16.

    Article  PubMed  CAS  Google Scholar 

  11. El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993;75:817–25.

    Article  PubMed  CAS  Google Scholar 

  12. Michieli P, Chedid M, Lin D, Pierce JH, Mercer WE, Givol D. Induction of WAF1/CIP1 by a p53-independent pathway. Cancer Res. 1994;54:3391–5.

    PubMed  CAS  Google Scholar 

  13. Akagi M, Yasui W, Akama Y, Yokozaki H, Tahara H, Haruma K, Kajiyama G, Tahara E. Inhibition of cell growth by transforming growth factor beta 1 is associated with p53-independent induction of p21 in gastric carcinoma cells. Jpn J Cancer Res. 1996;87:377–84.

    Article  PubMed  CAS  Google Scholar 

  14. Yasui W, Akama Y, Kuniyasu H, Yokozaki H, Semba S, Shimamoto F, Tahara E. Expression of cyclin-dependent kinase inhibitor p21WAF1/CIP1 in non-neoplastic mucosa and neoplasia of the stomach: relationship with p53 status and proliferative activity. J Pathol. 1996;180:122–8.

    Article  PubMed  CAS  Google Scholar 

  15. Xie HL, Su Q, He XS, Liang XO, Zhou JG, Song Y. Expression of p21WAF1 and p53 and polymorphismof p21WAF1gene in gastric carcinoma. World J Gastroenterol. 2004;10:1125–31.

    PubMed  CAS  Google Scholar 

  16. Ogawa M, Maeda K, Onoda N, Chung Y-S, Sowa M. Loss of p21 espression correlates with disease progression in gastric carcinoma. Br J Cancer. 1997;75:1617–20.

    Article  PubMed  CAS  Google Scholar 

  17. Seo YH, Joo YE, Choi SK, Rew JS, Park CS, Kim SJ. Prognostic significance of p21 and p53 expression in gastric cancer. Korean J Intern Med. 2003;18:98–103.

    PubMed  CAS  Google Scholar 

  18. Mizokami K, Kakeji Y, Oda S, Maehara Y. Relationship of hypoxia-inducible factor 1α and p21WAF1/CIP1 expression to cell apoptosis and clinical outcome in patients with gastric cancer. World J Surg Oncol. 2006;4:94–101.

    Article  PubMed  Google Scholar 

  19. Gomyo Y, Ikeda M, Osaki M, Tatebe S, Tsujitani S, Ikeguchi M, Kaibara N, Ito H. Expression of p21, but not p53 protein, is a factor in the survival of patients with advanced gastric carcinoma. Cancer. 1997;79:2067–72.

    Article  PubMed  CAS  Google Scholar 

  20. Müller W, Noguchi T, Wirtz HC, Hommel G, Gabbert HE. Expression of cell-cycle regulatory proteins cyclin D1, cyclin E, and their inhibitor p21 WAF1/CIP1 in gastric cancer. J Pathol. 1999;189:186–93.

    Article  PubMed  Google Scholar 

  21. Park YE, Choi KC, Choi YH. p21 expression and mutation in gastric carcinoma: analysis by immunohistochemistry and PCR-SSCP. J Korean Med Sci. 1998;13:507–12.

    PubMed  CAS  Google Scholar 

  22. Chariylertsak S, Sugano K, Ohkura H, Mari Y. Comparison of c-erbB-2 oncoprotein expression in tissue and serum of patients with stomach cancer. Tumour Biol. 1994;15:294–303.

    Article  Google Scholar 

  23. Yonemura Y, Ninomiya I, Yamaguchi A. Evalution of immünreactivity for c-erbB-2 protein as a marker of poor short term prognosis in gastric cancer. Cancer Res. 1991;51:1034–8.

    PubMed  CAS  Google Scholar 

  24. Yonemura Y, Ninomiya I, Ohoyama S, Kimura H, Yamaguchi A, Fushida S, Kosaka T, Miwa K, Miyazaki I, Endou Y. Expression of c-erbB-2 oncoprotein in gastric carcinoma. İmmünreactivity for c-erbB-2 protein is an indipentent indicatör of poor short–term prognosis in patients with gastric carcinoma. Cancer. 1991;67:2914–8.

    Article  PubMed  CAS  Google Scholar 

  25. Mizutani T, Onda M, Tokunaga A, Yamanaka N, Sugisaki Y. Relationship of c-erbB-2 protein expression and gene amplification to invasion and metastasis in human gastric cancer. Cancer. 1993;72:2083–8.

    Article  PubMed  CAS  Google Scholar 

  26. Satiroglu-Tufan NL, Bir F, Calli-Demirkan N. Investigation of HER-2 codon 655 single nucleotide polymorphism frequency and c-ErbB-2 protein expression alterations in gastric cancer patients. World J Gastroenterol. 2006;12:3283–7.

    PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by Trakya University Scientific Research Projects Unit in the program year of 2010.

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Correspondence to Alaattin Ozen.

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Ozen, A., Kocak, Z., Sipahi, T. et al. The prognostic significance of p21 and Her-2 gene expression and mutation/polymorphism in patients with gastric adenocarcinoma. Med Oncol 30, 357 (2013). https://doi.org/10.1007/s12032-012-0357-y

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  • DOI: https://doi.org/10.1007/s12032-012-0357-y

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