Three-gene predictor of clinical outcome for gastric cancer patients treated with chemotherapy

To identify transcriptional profiles predictive of the clinical benefit of cisplatin and fluorouracil (CF) chemotherapy to gastric cancer patients, endoscopic biopsy samples from 96 CF-treated metastatic gastric cancer patients were prospectively collected before therapy and analyzed using high-throughput transcriptional profiling and array comparative genomic hybridization. Transcriptional profiling identified 917 genes that are correlated with poor patient survival after CF at P<0.05 (poor prognosis signature), in which protein synthesis and DNA replication/recombination/repair functional categories are enriched. A survival risk predictor was then constructed using genes, which are included in the poor prognosis signature and are contained within identified genomic amplicons. The combined expression of three genes—MYC, EGFR and FGFR2—was an independent predictor for overall survival of 27 CF-treated patients in the validation set (adjusted P=0.017), and also for survival of 40 chemotherapy-treated gastric cancer patients in a published data set (adjusted P=0.026). Thus, combined expression of MYC, EGFR and FGFR2 is predictive of poor survival in CF-treated metastatic gastric cancer patients.

[1]  Russ B. Altman,et al.  Missing value estimation methods for DNA microarrays , 2001, Bioinform..

[2]  R. Simon,et al.  Effectiveness of gene expression profiling for response prediction of rectal adenocarcinomas to preoperative chemoradiotherapy. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  M. Yashiro,et al.  Synergistic antitumor effects of FGFR2 inhibitor with 5‐fluorouracil on scirrhous gastric carcinoma , 2009, International journal of cancer.

[4]  J. Baselga,et al.  Antitumor effect of anti-epidermal growth factor receptor monoclonal antibodies plus cis-diamminedichloroplatinum on well established A431 cell xenografts. , 1993, Cancer research.

[5]  A. Bardia,et al.  Hand-foot syndrome after dose-dense adjuvant chemotherapy for breast cancer: a case series. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  A. Norman,et al.  Randomised multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric (OG) cancer: The REAL 2 trial. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  Rui Li,et al.  Phospholipase A2 group IIA expression in gastric adenocarcinoma is associated with prolonged survival and less frequent metastasis , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Zhaoming Ye,et al.  Recombinant Antisense C-myc Adenovirus Increase in vitro Sensitivity of Osteosarcoma MG-63 Cells to Cisplatin , 2006, Cancer investigation.

[9]  P. Iversen,et al.  Resistance to chemotherapeutic drugs overcome by c-Myc inhibition in a Lewis lung carcinoma murine model , 2003, Anti-cancer drugs.

[10]  Il-Jin Kim,et al.  DNA microarray analysis of the correlation between gene expression patterns and acquired resistance to 5-FU/cisplatin in gastric cancer. , 2004, Biochemical and biophysical research communications.

[11]  M. Lichinitser,et al.  Randomized phase III trial of capecitabine/cisplatin (XP) vs. continuous infusion of 5-FU/cisplatin (FP) as first-line therapy in patients (pts) with advanced gastric cancer (AGC): Efficacy and safety results. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  M. Radmacher,et al.  Design of studies using DNA microarrays , 2002, Genetic epidemiology.

[13]  J. Willey,et al.  ABCC5, ERCC2, XPA and XRCC1 transcript abundance levels correlate with cisplatin chemoresistance in non-small cell lung cancer cell lines , 2005, Molecular Cancer.

[14]  Anne-Laure Boulesteix,et al.  Microarray-based prediction of tumor response to neoadjuvant radiochemotherapy of patients with locally advanced rectal cancer. , 2008, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[15]  H. K. Kim,et al.  Phase II study of docetaxel and irinotecan combination chemotherapy in metastatic gastric carcinoma , 2006, British Journal of Cancer.

[16]  R. Seruca,et al.  Bmc Cancer Epidermal Growth Factor Receptor Structural Alterations in Gastric Cancer , 2022 .

[17]  N. Lee,et al.  Identification of c-myc responsive genes using rat cDNA microarray. , 2000, Cancer research.

[18]  K. Yanagihara,et al.  Amplification of c-myc, K-sam, and c-met in gastric cancers: detection by fluorescence in situ hybridization. , 1998, Laboratory investigation; a journal of technical methods and pathology.

[19]  Yung-Yen Chiang,et al.  Nuclear expression of dynamin-related protein 1 in lung adenocarcinomas , 2009, Modern Pathology.

[20]  R. Tibshirani,et al.  Semi-Supervised Methods to Predict Patient Survival from Gene Expression Data , 2004, PLoS biology.

[21]  Masahiro Fukuoka,et al.  Synergistic antitumor effect of S-1 and the epidermal growth factor receptor inhibitor gefitinib in non-small cell lung cancer cell lines: role of gefitinib-induced down-regulation of thymidylate synthase , 2008, Molecular Cancer Therapeutics.

[22]  Zhaoming Ye,et al.  [Construction of antisense c-myc recombinant adenovirus and its anti-tumor effects on osteosarcoma cell lines MG-63 and U2OS]. , 2005, Ai zheng = Aizheng = Chinese journal of cancer.

[23]  P. Johnston,et al.  Clinical Determinants of Response to Irinotecan-Based Therapy Derived from Cell Line Models , 2008, Clinical Cancer Research.

[24]  J. Grem,et al.  Thymidylate synthase, dihydropyrimidine dehydrogenase, ERCC1, and thymidine phosphorylase gene expression in primary and metastatic gastrointestinal adenocarcinoma tissue in patients treated on a phase I trial of oxaliplatin and capecitabine , 2008, BMC Cancer.

[25]  S. Groshen,et al.  ERCC1 mRNA levels complement thymidylate synthase mRNA levels in predicting response and survival for gastric cancer patients receiving combination cisplatin and fluorouracil chemotherapy. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  C. J. Lowe,et al.  Thalidomide use and digital gangrene. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  Robert C. Wolpert,et al.  A Review of the , 1985 .

[28]  C. Mathew,et al.  Disruption of the Fanconi anemia–BRCA pathway in cisplatin-sensitive ovarian tumors , 2003, Nature Medicine.

[29]  M. Orditura,et al.  Expression of Vascular Endothelial Growth Factor (VEGF) and Epidermal Growth Factor Receptor (EGFR) is an Independent Prognostic Indicator of Worse Outcome in Gastric Cancer Patients , 2007, Annals of Surgical Oncology.

[30]  J. Balko,et al.  A gene expression predictor of response to EGFR-targeted therapy stratifies progression-free survival to cetuximab in KRAS wild-type metastatic colorectal cancer , 2009, BMC Cancer.

[31]  G. Zupi,et al.  Glutathione depletion induced by c-Myc downregulation triggers apoptosis on treatment with alkylating agents. , 2004, Neoplasia.

[32]  T. Gotoda,et al.  Identification of prognostic biomarkers in gastric cancer using endoscopic biopsy samples , 2008, Cancer science.

[33]  C. Leonetti,et al.  Increase of cisplatin sensitivity by c-myc antisense oligodeoxynucleotides in a human metastatic melanoma inherently resistant to cisplatin. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[34]  Yingdong Zhao,et al.  Analysis of Gene Expression Data Using BRB-Array Tools , 2007, Cancer informatics.

[35]  S. Groshen,et al.  Thymidylate synthase mRNA level in adenocarcinoma of the stomach: a predictor for primary tumor response and overall survival. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[36]  Hirofumi Nakayama,et al.  Molecular-pathological prognostic factors of gastric cancer: a review , 2005, Gastric Cancer.

[37]  S. Pyrhönen,et al.  Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer. , 1995, British Journal of Cancer.

[38]  H. Sakamoto,et al.  Amplified genes in cancer in upper digestive tract. , 1993, Seminars in cancer biology.

[39]  Kevin K Dobbin,et al.  Optimally splitting cases for training and testing high dimensional classifiers , 2011, BMC Medical Genomics.

[40]  I. Choi,et al.  Phase II Study of Low-Dose Docetaxel/Fluorouracil/Cisplatin in Metastatic Gastric Carcinoma , 2005, American journal of clinical oncology.