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Erschienen in: Medical Oncology 3/2013

01.09.2013 | Original Paper

Identification of a 5-gene signature for clinical and prognostic prediction in gastric cancer patients upon microarray data

verfasst von: Zhigang Wang, Zhi Yan, Bicheng Zhang, Zhiguo Rao, Yafei Zhang, Jian Liu, Lifang Yu, Yong Zhao, Bo Yang, Tingting Wu, Jianfei Gao

Erschienen in: Medical Oncology | Ausgabe 3/2013

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Abstract

In this study, we aimed to investigate the clinical and prognostic value of a 5-gene expression signature model for gastric cancer patients upon microarray data. A total of 158 gastric cancer patients were selected, with 33 cases used for microarray analysis as training set and 125 cases for validation real-time quantitative polymerase chain reaction analysis as test set. Unsupervised clustering algorithms and supervised clustering algorithm were used to identify differentially expressed genes. Gene ontology analyses were used to determine functional prediction of gene biomarkers and receiver operating characteristic analyses to verify the specificity and sensitivity of the evaluation. Moreover, the correlation between clinicopathological characteristics and 5-gene expression was evaluated. The results showed that there were poor disease progression and clinic prognosis in the patients with proximal gastric cancer compared with distal gastric cancer, including differentiation grade (P = 0.001), depth of tumor invasion (P < 0.01), lymph node metastasis (P < 0.01), UICC stage (P < 0.01), and survival status (P < 0.01). Furthermore, a 5-gene signature, including cordon-bleu protein-like 1, damage-specific DNA binding protein 1, BCL2-like 13, nuclear receptor coactivator-6, and F-box leucine-rich protein 11, was identified based on the combination of multiple bioinformatics algorithm. The expression of 5-gene signature (HR = 2.35; 95 % confidence interval 1.24–5.06; P = 0.026) and UICC stage (HR = 5.35; 95 % confidence interval 1.36–19.15; P = 0.032) was independent prognostic factors for overall survival in the survival multivariate analysis. Over-expression of the 5-gene signature in patients with proximal gastric cancer is strongly associated with disease progression and poor prognosis, suggesting that might be potential prognostic predictors in gastric cancer.
Literatur
1.
Zurück zum Zitat Vial M, Grande L, Pera M. Epidemiology of adenocarcinoma of the esophagus, gastric cardia, and upper gastric third. Recent Results Cancer Res. 2010;182:1–17.PubMedCrossRef Vial M, Grande L, Pera M. Epidemiology of adenocarcinoma of the esophagus, gastric cardia, and upper gastric third. Recent Results Cancer Res. 2010;182:1–17.PubMedCrossRef
2.
Zurück zum Zitat Souza RF, Spechler SJ. Concepts in the prevention of adenocarcinoma of the distal esophagus and proximal stomach. CA Cancer J Clin. 2005;55:334–51.PubMedCrossRef Souza RF, Spechler SJ. Concepts in the prevention of adenocarcinoma of the distal esophagus and proximal stomach. CA Cancer J Clin. 2005;55:334–51.PubMedCrossRef
3.
Zurück zum Zitat Schlansky B, Sonnenberg A. Epidemiology of noncardia gastric adenocarcinoma in the United States. Am J Gastroenterol. 2011;106:1978–85.PubMedCrossRef Schlansky B, Sonnenberg A. Epidemiology of noncardia gastric adenocarcinoma in the United States. Am J Gastroenterol. 2011;106:1978–85.PubMedCrossRef
4.
Zurück zum Zitat Kunz PL, Gubens M, Fisher GA, Ford JM, Lichtensztajn DY, Clarke CA. Long-term survivors of gastric cancer: a California population-based study. J Clin Oncol. 2012;30:3507–15.PubMedCrossRef Kunz PL, Gubens M, Fisher GA, Ford JM, Lichtensztajn DY, Clarke CA. Long-term survivors of gastric cancer: a California population-based study. J Clin Oncol. 2012;30:3507–15.PubMedCrossRef
5.
Zurück zum Zitat Maeda H, Okabayashi T, Nishimori I, Sugimoto T, Namikawa T, Dabanaka K, et al. Clinicopathologic features of adenocarcinoma at the gastric cardia: is it different from distal cancer of the stomach? J Am Coll Surg. 2008;206:306–10.PubMedCrossRef Maeda H, Okabayashi T, Nishimori I, Sugimoto T, Namikawa T, Dabanaka K, et al. Clinicopathologic features of adenocarcinoma at the gastric cardia: is it different from distal cancer of the stomach? J Am Coll Surg. 2008;206:306–10.PubMedCrossRef
6.
Zurück zum Zitat Shah MA, Khanin R, Tang L, Janjigian YY, Klimstra DS, Gerdes H, et al. Molecular classification of gastric cancer: a new paradigm. Clin Cancer Res. 2011;17:2693–701.PubMedCrossRef Shah MA, Khanin R, Tang L, Janjigian YY, Klimstra DS, Gerdes H, et al. Molecular classification of gastric cancer: a new paradigm. Clin Cancer Res. 2011;17:2693–701.PubMedCrossRef
7.
Zurück zum Zitat DeMeester SR. Adenocarcinoma of the esophagus and cardia: a review of the disease and its treatment. Ann Surg Oncol. 2006;13:12–30.PubMedCrossRef DeMeester SR. Adenocarcinoma of the esophagus and cardia: a review of the disease and its treatment. Ann Surg Oncol. 2006;13:12–30.PubMedCrossRef
8.
Zurück zum Zitat Dirican A, Ekinci N, Avci A, Akyol M, Alacacioglu A, Kucukzeybek Y, et al. The effects of hematological parameters and tumor-infiltrating lymphocytes on prognosis in patients with gastric cancer. Cancer Biomark. 2013;13:11–20.PubMed Dirican A, Ekinci N, Avci A, Akyol M, Alacacioglu A, Kucukzeybek Y, et al. The effects of hematological parameters and tumor-infiltrating lymphocytes on prognosis in patients with gastric cancer. Cancer Biomark. 2013;13:11–20.PubMed
9.
Zurück zum Zitat Zheng Y, Cui L, Sun W, Zhou H, Yuan X, Huo M, et al. MicroRNA-21 is a new marker of circulating tumor cells in gastric cancer patients. Cancer Biomark. 2011–2012; 10:71–7. Zheng Y, Cui L, Sun W, Zhou H, Yuan X, Huo M, et al. MicroRNA-21 is a new marker of circulating tumor cells in gastric cancer patients. Cancer Biomark. 2011–2012; 10:71–7.
10.
Zurück zum Zitat Pietrantonio F, De Braud F, Da Prat V, Perrone F, Pierotti MA, Gariboldi M, et al. A review on biomarkers for prediction of treatment outcome in gastric cancer. Anticancer Res. 2013;33:1257–66.PubMed Pietrantonio F, De Braud F, Da Prat V, Perrone F, Pierotti MA, Gariboldi M, et al. A review on biomarkers for prediction of treatment outcome in gastric cancer. Anticancer Res. 2013;33:1257–66.PubMed
11.
Zurück zum Zitat Rossi E, Klersy C, Manca R, Zuffardi O, Solcia E. Correlation between genomic alterations assessed by array comparative genomic hybridization, prognostically informative histologic subtype, stage, and patient survival in gastric cancer. Hum Pathol. 2011;42:1937–45.PubMedCrossRef Rossi E, Klersy C, Manca R, Zuffardi O, Solcia E. Correlation between genomic alterations assessed by array comparative genomic hybridization, prognostically informative histologic subtype, stage, and patient survival in gastric cancer. Hum Pathol. 2011;42:1937–45.PubMedCrossRef
12.
Zurück zum Zitat Takeno A, Takemasa I, Doki Y, Yamasaki M, Miyata H, Takiguchi S, et al. Integrative approach for differentially overexpressed genes in gastric cancer by combining large-scale gene expression profiling and network analysis. Br J Cancer. 2008;99:1307–15.PubMedCrossRef Takeno A, Takemasa I, Doki Y, Yamasaki M, Miyata H, Takiguchi S, et al. Integrative approach for differentially overexpressed genes in gastric cancer by combining large-scale gene expression profiling and network analysis. Br J Cancer. 2008;99:1307–15.PubMedCrossRef
13.
Zurück zum Zitat Wang Q, Wen YG, Li DP, Xia J, Zhou CZ, Yan DW, et al. Upregulated INHBA expression is associated with poor survival in gastric cancer. Med Oncol. 2012;29:77–83.PubMedCrossRef Wang Q, Wen YG, Li DP, Xia J, Zhou CZ, Yan DW, et al. Upregulated INHBA expression is associated with poor survival in gastric cancer. Med Oncol. 2012;29:77–83.PubMedCrossRef
14.
Zurück zum Zitat Park Y, Kang MH, Seo HY, Park JM, Choi CW, Kim YH, et al. Bone morphogenetic protein-2 levels are elevated in the patients with gastric cancer and correlate with disease progression. Med Oncol. 2010;27:1192–9.PubMedCrossRef Park Y, Kang MH, Seo HY, Park JM, Choi CW, Kim YH, et al. Bone morphogenetic protein-2 levels are elevated in the patients with gastric cancer and correlate with disease progression. Med Oncol. 2010;27:1192–9.PubMedCrossRef
15.
Zurück zum Zitat Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001;25:402–8.PubMedCrossRef Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001;25:402–8.PubMedCrossRef
16.
Zurück zum Zitat Tusher VG, Tibshirani R, Chu G. Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci U S A. 2001;98:5116–21.PubMedCrossRef Tusher VG, Tibshirani R, Chu G. Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci U S A. 2001;98:5116–21.PubMedCrossRef
17.
Zurück zum Zitat Meiklejohn CD, Townsend JP. A Bayesian method for analysing spotted microarray data. Brief Bioinform. 2005;6:318–30.PubMedCrossRef Meiklejohn CD, Townsend JP. A Bayesian method for analysing spotted microarray data. Brief Bioinform. 2005;6:318–30.PubMedCrossRef
18.
Zurück zum Zitat Pepe MS, Longton G, Anderson GL, Schummer M. Selecting differentially expressed genes from microarray experiments. Biometrics. 2003;59:133–42.PubMedCrossRef Pepe MS, Longton G, Anderson GL, Schummer M. Selecting differentially expressed genes from microarray experiments. Biometrics. 2003;59:133–42.PubMedCrossRef
19.
Zurück zum Zitat Eisen MB, Spellman PT, Brown PO, Botstein D. Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci U S A. 1998;95:14863–8.PubMedCrossRef Eisen MB, Spellman PT, Brown PO, Botstein D. Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci U S A. 1998;95:14863–8.PubMedCrossRef
20.
Zurück zum Zitat Panani AD. Cytogenetic and molecular aspects of gastric cancer: clinical implications. Cancer Lett. 2008;266:99–115.PubMedCrossRef Panani AD. Cytogenetic and molecular aspects of gastric cancer: clinical implications. Cancer Lett. 2008;266:99–115.PubMedCrossRef
21.
Zurück zum Zitat Tajima Y, Yamazaki K, Makino R, Nishino N, Masuda Y, Aoki S, et al. Differences in the histological findings, phenotypic marker expressions and genetic alterations between adenocarcinoma of the gastric cardia and distal stomach. Br J Cancer. 2007;96:631–8.PubMedCrossRef Tajima Y, Yamazaki K, Makino R, Nishino N, Masuda Y, Aoki S, et al. Differences in the histological findings, phenotypic marker expressions and genetic alterations between adenocarcinoma of the gastric cardia and distal stomach. Br J Cancer. 2007;96:631–8.PubMedCrossRef
22.
Zurück zum Zitat Chen Z, Saad R, Jia P, Peng D, Zhu S, Washington MK, et al. Gastric adenocarcinoma has a unique microRNA signature not present in esophageal adenocarcinoma. Cancer. 2013;119:1985–93.PubMedCrossRef Chen Z, Saad R, Jia P, Peng D, Zhu S, Washington MK, et al. Gastric adenocarcinoma has a unique microRNA signature not present in esophageal adenocarcinoma. Cancer. 2013;119:1985–93.PubMedCrossRef
23.
Zurück zum Zitat Cho JY, Lim JY, Cheong JH, Park YY, Yoon SL, Kim SM, et al. Gene expression signature-based prognostic risk score in gastric cancer. Clin Cancer Res. 2011;17:1850–7.PubMedCrossRef Cho JY, Lim JY, Cheong JH, Park YY, Yoon SL, Kim SM, et al. Gene expression signature-based prognostic risk score in gastric cancer. Clin Cancer Res. 2011;17:1850–7.PubMedCrossRef
24.
Zurück zum Zitat Wang G, Hu N, Yang HH, Wang L, Su H, Wang C, et al. Comparison of global gene expression of gastric cardia and noncardia cancers from a high-risk population in china. PLoS ONE. 2013;8:e63826.PubMedCrossRef Wang G, Hu N, Yang HH, Wang L, Su H, Wang C, et al. Comparison of global gene expression of gastric cardia and noncardia cancers from a high-risk population in china. PLoS ONE. 2013;8:e63826.PubMedCrossRef
25.
Zurück zum Zitat Komatsu S, Ichikawa D, Okamoto K, Ikoma D, Tsujiura M, Shiozaki A, et al. Differences of the lymphatic distribution and surgical outcomes between remnant gastric cancers and primary proximal gastric cancers. J Gastrointest Surg. 2012;16:503–8.PubMedCrossRef Komatsu S, Ichikawa D, Okamoto K, Ikoma D, Tsujiura M, Shiozaki A, et al. Differences of the lymphatic distribution and surgical outcomes between remnant gastric cancers and primary proximal gastric cancers. J Gastrointest Surg. 2012;16:503–8.PubMedCrossRef
26.
Zurück zum Zitat Wilkinson NW, Howe J, Gay G, Patel-Parekh L, Scott-Conner C, Donohue J. Differences in the pattern of presentation and treatment of proximal and distal gastric cancer: results of the 2001 gastric patient care evaluation. Ann Surg Oncol. 2008;15:1644–50.PubMedCrossRef Wilkinson NW, Howe J, Gay G, Patel-Parekh L, Scott-Conner C, Donohue J. Differences in the pattern of presentation and treatment of proximal and distal gastric cancer: results of the 2001 gastric patient care evaluation. Ann Surg Oncol. 2008;15:1644–50.PubMedCrossRef
27.
Zurück zum Zitat Herceg Z, Hainaut P. Genetic and epigenetic alterations as biomarkers for cancer detection, diagnosis and prognosis. Mol Oncol. 2007;1:26–41.PubMedCrossRef Herceg Z, Hainaut P. Genetic and epigenetic alterations as biomarkers for cancer detection, diagnosis and prognosis. Mol Oncol. 2007;1:26–41.PubMedCrossRef
28.
Zurück zum Zitat Gordon GJ, Dong L, Yeap BY, Richards WG, Glickman JN, Edenfield H, et al. Four-gene expression ratio test for survival in patients undergoing surgery for mesothelioma. J Natl Cancer Inst. 2009;101:678–86.PubMedCrossRef Gordon GJ, Dong L, Yeap BY, Richards WG, Glickman JN, Edenfield H, et al. Four-gene expression ratio test for survival in patients undergoing surgery for mesothelioma. J Natl Cancer Inst. 2009;101:678–86.PubMedCrossRef
29.
Zurück zum Zitat Yamaji S, Zhang M, Zhang J, Endo Y, Bibikova E, Goff SP, et al. Hepatocyte-specific deletion of DDB1 induces liver regeneration and tumorigenesis. Proc Natl Acad Sci U S A. 2010;107:22237–42.PubMedCrossRef Yamaji S, Zhang M, Zhang J, Endo Y, Bibikova E, Goff SP, et al. Hepatocyte-specific deletion of DDB1 induces liver regeneration and tumorigenesis. Proc Natl Acad Sci U S A. 2010;107:22237–42.PubMedCrossRef
30.
Zurück zum Zitat Hu J, McCall CM, Ohta T, Xiong Y. Targeted ubiquitination of CDT1 by the DDB1-CUL4A-ROC1 ligase in response to DNA damage. Nat Cell Biol. 2004;6:1003–9.PubMedCrossRef Hu J, McCall CM, Ohta T, Xiong Y. Targeted ubiquitination of CDT1 by the DDB1-CUL4A-ROC1 ligase in response to DNA damage. Nat Cell Biol. 2004;6:1003–9.PubMedCrossRef
31.
Zurück zum Zitat Yang SH, Seo MY, Jeong HJ, Jeung HC, Shin J, Kim SC, et al. Gene copy number change events at chromosome 20 and their association with recurrence in gastric cancer patients. Clin Cancer Res. 2005;11:612–20.PubMed Yang SH, Seo MY, Jeong HJ, Jeung HC, Shin J, Kim SC, et al. Gene copy number change events at chromosome 20 and their association with recurrence in gastric cancer patients. Clin Cancer Res. 2005;11:612–20.PubMed
32.
Zurück zum Zitat Li Q, Xu J. Identification and characterization of the alternatively spliced nuclear receptor coactivator-6 isoforms. Int J Biol Sci. 2011;7:505–16.PubMedCrossRef Li Q, Xu J. Identification and characterization of the alternatively spliced nuclear receptor coactivator-6 isoforms. Int J Biol Sci. 2011;7:505–16.PubMedCrossRef
33.
Zurück zum Zitat Mahajan MA, Samuels HH. Nuclear receptor coactivator/coregulator NCoA6 (NRC) is a pleiotropic coregulator involved in transcription, cell survival, growth and development. Nucl Recept Signal. 2008;6:e002.PubMed Mahajan MA, Samuels HH. Nuclear receptor coactivator/coregulator NCoA6 (NRC) is a pleiotropic coregulator involved in transcription, cell survival, growth and development. Nucl Recept Signal. 2008;6:e002.PubMed
34.
Zurück zum Zitat Yi P, Zhang W, Zhai Z, Miao L, Wang Y, Wu M. Bcl-rambo beta, a special splicing variant with an insertion of an Alu-like cassette, promotes etoposide- and Taxol-induced cell death. FEBS Lett. 2003;534:61–8.PubMedCrossRef Yi P, Zhang W, Zhai Z, Miao L, Wang Y, Wu M. Bcl-rambo beta, a special splicing variant with an insertion of an Alu-like cassette, promotes etoposide- and Taxol-induced cell death. FEBS Lett. 2003;534:61–8.PubMedCrossRef
35.
Zurück zum Zitat Holleman A, den Boer ML, de Menezes RX, Cheok MH, Cheng C, Kazemier KM, et al. The expression of 70 apoptosis genes in relation to lineage, genetic subtype, cellular drug resistance, and outcome in childhood acute lymphoblastic leukemia. Blood. 2006;107:769–76.PubMedCrossRef Holleman A, den Boer ML, de Menezes RX, Cheok MH, Cheng C, Kazemier KM, et al. The expression of 70 apoptosis genes in relation to lineage, genetic subtype, cellular drug resistance, and outcome in childhood acute lymphoblastic leukemia. Blood. 2006;107:769–76.PubMedCrossRef
36.
Zurück zum Zitat Petry IB, Fieber E, Schmidt M, Gehrmann M, Gebhard S, Hermes M, et al. ERBB2 induces an antiapoptotic expression pattern of Bcl-2 family members in node-negative breast cancer. Clin Cancer Res. 2010;16:451–60.PubMedCrossRef Petry IB, Fieber E, Schmidt M, Gehrmann M, Gebhard S, Hermes M, et al. ERBB2 induces an antiapoptotic expression pattern of Bcl-2 family members in node-negative breast cancer. Clin Cancer Res. 2010;16:451–60.PubMedCrossRef
37.
Zurück zum Zitat Lu T, Jackson MW, Singhi AD, Kandel ES, Yang M, Zhang Y, et al. Validation-based insertional mutagenesis identifies lysine demethylase FBXL11 as a negative regulator of NFkappaB. Proc Natl Acad Sci U S A. 2009;106:16339–44.PubMedCrossRef Lu T, Jackson MW, Singhi AD, Kandel ES, Yang M, Zhang Y, et al. Validation-based insertional mutagenesis identifies lysine demethylase FBXL11 as a negative regulator of NFkappaB. Proc Natl Acad Sci U S A. 2009;106:16339–44.PubMedCrossRef
38.
Zurück zum Zitat Lu T, Jackson MW, Wang B, Yang M, Chance MR, Miyagi M, et al. Regulation of NF-kappaB by NSD1/FBXL11-dependent reversible lysine methylation of p65. Proc Natl Acad Sci U S A. 2010;107:46–51.PubMedCrossRef Lu T, Jackson MW, Wang B, Yang M, Chance MR, Miyagi M, et al. Regulation of NF-kappaB by NSD1/FBXL11-dependent reversible lysine methylation of p65. Proc Natl Acad Sci U S A. 2010;107:46–51.PubMedCrossRef
Metadaten
Titel
Identification of a 5-gene signature for clinical and prognostic prediction in gastric cancer patients upon microarray data
verfasst von
Zhigang Wang
Zhi Yan
Bicheng Zhang
Zhiguo Rao
Yafei Zhang
Jian Liu
Lifang Yu
Yong Zhao
Bo Yang
Tingting Wu
Jianfei Gao
Publikationsdatum
01.09.2013
Verlag
Springer US
Erschienen in
Medical Oncology / Ausgabe 3/2013
Print ISSN: 1357-0560
Elektronische ISSN: 1559-131X
DOI
https://doi.org/10.1007/s12032-013-0678-5

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