Objectives: The aim of this study was to identify biomarkers for predicting the efficacy of docetaxel, cisplatin, and S-1 (DCS) therapy for advanced gastric cancer using microarrays of biopsy specimens before chemotherapy. Methods: Nineteen samples were taken from 19 patients with unresectable metastatic gastric cancer who received DCS as a first-line therapy. Laser capture microdissection was performed, and total cellular RNA was extracted from each microdissected sample. Whole-gene expression was analyzed by microarray, and the difference in mRNA expression observed with the microarrays was confirmed by quantitative real-time PCR. Immunohistochemical staining was performed using clinical tissue sections obtained by endoscopic biopsy. Results: Eleven patients were identified as early responders and 8 patients as nonresponders to DCS therapy. Twenty-nine genes showed significant differences in relative expression ratios between tumor and normal tissues. A classifier set of 29 genes had high accuracy (94.7%) for distinguishing gene expression between 11 early responders and 8 nonresponders. Decreasing the size of the classifier set to 4 genes (PDGFB, PCGF3, CISH, and ANXA5) increased the accuracy to 100%. Expression levels by real-time PCR for validation were well correlated with those 4 genes in microarrays. Conclusion: The genes identified may serve as efficient biomarkers for personalized cancer-targeted therapy.

Keywords:
Gastric cancer, Microarray, Chemotherapy
1.
Tanaka M, Ma E, Tanaka H, Ioka A, Nakahara T, Takahashi H: Trends of stomach cancer mortality in Eastern Asia in 1950-2004: comparative study of Japan, Hong Kong and Singapore using age, period and cohort analysis. Int J Cancer 2012;130:930-936.
2.
Katanoda K, Hori M, Matsuda T, Shibata A, Nishino Y, Hattori M, Soda M, Ioka A, Sobue T, Nishimoto H: An updated report on the trends in cancer incidence and mortality in Japan, 1958-2013. Jpn J Clin Oncol 2015;45:390-401.
3.
Webb A, Cunningham D, Scarffe JH, Harper P, Norman A, Joffe JK, Hughes M, Mansi J, Findlay M, Hill A, Oates J, Nicolson M, Hickish T, Obrien M, Iveson T, Watson M, Underhill C, Wardley A, Meehan M: Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 1997;15:261-267.
4.
Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, Risse M-L, Ajani JA: Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol 2006;24:4991-4997.
5.
Kilickap S, Yalcin S, Ates O, Tekuzman G: The first line systemic chemotherapy in metastatic gastric carcinoma: a comparison of docetaxel, cisplatin and fluorouracil (DCF) versus cisplatin and fluorouracil (CF); versus epirubicin, cisplatin and fluorouracil (ECF) regimens in clinical setting. Hepatogastroenterology 2011;58:208-212.
6.
Takayama T, Sato Y, Sagawa T, Okamoto T, Nagashima H, Takahashi Y, Ohnuma H, Kuroiwa G, Miyanishi K, Takimoto R, Matsunaga T, Kato J, Yamaguchi K, Hirata K, Niitsu Y: Phase I study of S-1, docetaxel and cisplatin combination chemotherapy in patients with unresectable metastatic gastric cancer. Br J Cancer 2007;97:851-856.
7.
Sato Y, Takayama T, Sagawa T, Takahashi Y, Ohnuma H, Okubo S, Shintani N, Tanaka S, Kida M, Sato Y, Ohta H, Miyanishi K, Sato T, Takimoto R, Kobune M, Yamaguchi K, Hirata K, Niitsu Y, Kato J: Phase II study of S-1, docetaxel and cisplatin combination chemotherapy in patients with unresectable metastatic gastric cancer. Cancer Chemother Pharmacol 2010;66:721-728.
8.
Koizumi W, Nakayama N, Tanabe S, Sasaki T, Higuchi K, Nishimura K, Takagi S, Azuma M, Ae T, Ishido K, Nakatani K, Naruke A, Katada C: A multicenter phase II study of combined chemotherapy with docetaxel, cisplatin, and S-1 in patients with unresectable or recurrent gastric cancer (KDOG 0601). Cancer Chemother Pharmacol 2012;69:407-413.
9.
Hirakawa M, Sato Y, Ohnuma H, Takayama T, Sagawa T, Nobuoka T, Harada K, Miyamoto H, Sato Y, Takahashi Y, Katsuki S, Hirayama M, Takahashi M, Ono M, Maeda M, Takada K, Hayashi T, Sato T, Miyanishi K, Takimoto R, Kobune M, Hirata K, Kato J: A phase II study of neoadjuvant combination chemotherapy with docetaxel, cisplatin, and S-1 for locally advanced resectable gastric cancer: nucleotide excision repair (NER) as potential chemoresistance marker. Cancer Chemother Pharmacol 2013;71:789-797.
10.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-247.
11.
Heinemann V, Stintzing S, Modest DP, Giessen-Jung C, Michl M, Mansmann UR: Early tumour shrinkage (ETS) and depth of response (DpR) in the treatment of patients with metastatic colorectal cancer (mCRC). Eur J Cancer 2015;51:1927-1936.
12.
Piessevaux H, Buyse M, Schlichting M, Van Cutsem E, Bokemeyer C, Heeger S, Tejpar S: Use of early tumor shrinkage to predict long-term outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol 2013;31:3764-3775.
13.
Asselah T, Bieche I, Narguet S, Sabbagh A, Laurendeau I, Ripault MP, Boyer N, Martinot-Peignoux M, Valla D, Vidaud M, Marcellin P: Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C. Gut 2008;57:516-524.
14.
Tuana G, Volpato V, Ricciardi-Castagnoli P, Zolezzi F, Stella F, Foti M: Classification of dendritic cell phenotypes from gene expression data. BMC Immunol 2011;12:50.
15.
Lim SM, Lim JY, Cho JY: Targeted therapy in gastric cancer: personalizing cancer treatment based on patient genome. World J Gastroenterol 2014;20:2042-2050.
16.
Zhang Y-H, Wu Q, Xiao X-Y, Li D-W, Wang X-P: Silencing MRP4 by small interfering RNA reverses acquired DDP resistance of gastric cancer cell. Cancer Lett 2010;291:76-82.
17.
Yu JH, Ustach C, Kim HRC: Platelet-derived growth factor signaling and human cancer. J Biochem Mol Biol 2003;36:49-59.
18.
Folkman J: Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995;1:27-31.
19.
Yoshimura A, Ohkubo T, Kiguchi T, Jenkins NA, Gilbert DJ, Copeland NG, Hara T, Miyajima A: A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors. EMBO J 1995;14:2816-2826.
20.
Borges S, Moudilou E, Vouyovitch C, Chiesa J, Lobie P, Mertani H, Raccurt M: Involvement of a JAK/STAT pathway inhibitor: cytokine inducible SH2 containing protein in breast cancer. Adv Exp Med Biol 2008;617:321-329.
21.
Zhou Y, Wan C, Liu Y, Lv L, Chen B, Ni R, Huang Y, Li Y, Zheng X, Yang D, Mao G, Xue Q: Polycomb group oncogene RING1 is over-expressed in non-small cell lung cancer. Pathol Oncol Res 2014;20:549-556.
22.
Gerke V, Creutz CE, Moss SE: Annexins: linking Ca2+ signalling to membrane dynamics. Nat Rev Mol Cell Biol 2005;6:449-461.
23.
Zhang ZD, Li Y, Fan LQ, Zhao Q, Tan BB, Zhao XF: Annexin A2 is implicated in multi-drug-resistance in gastric cancer through p38MAPK and AKT pathway. Neoplasma 2014;61:627-637.
24.
Peng B, Guo C, Guan H, Liu S, Sun M-Z: Annexin A5 as a potential marker in tumors. Clin Chim Acta 2014;427:42-48.
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2017
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