Pathway analysis of gene lists associated with platinum-based chemotherapy resistance in ovarian cancer: the big picture.

OBJECTIVE Ovarian cancer is the leading cause of death from gynecological cancers in the Western world (Parkin et al., 2005). The overall 5-year survival is only 30% (Moss and Kaye, 2002), which is for a significant part due to platinum-based chemotherapy resistance. In this study, we performed a pathway analysis on nine published gene sets associated with platinum resistance in ovarian cancer, including a study by us. With this exploratory study, we aim to identify overlapping pathways associated with platinum-based chemotherapy resistance mechanisms in ovarian cancer. METHODS Gene Ontology (GO) analysis and Ingenuity Pathway Analysis (IPA) were performed to determine which functional processes were differentially represented in the combined gene lists of nine studies (457 genes) compared to all Unigene identifiers or the Ingenuity knowledge base. RESULTS The GO and IPA analysis resulted in the generation of 23 gene networks, and showed that 13 GO processes (>or=2 times enriched), 71 canonical pathways (p<0.05,), eight toxicity pathways (p<0.05) and 74 biological functions (p<0.005) are significantly associated with the 9-study gene set. CONCLUSION AND RECOMMENDATIONS Several pathways identified have previously been shown to be associated with therapy resistance: these include 'oxidative stress response mediated by Nrf2,' 'TP53 signaling' and 'TGFbeta signaling.' The role of TGFbeta signaling and related miRNAs identified in the network analysis in epithelial-to-mesenchymal transition (EMT) and stemness as well as the possible relation with platin-based chemotherapy resistance are further discussed in detail. We propose that future international cooperation should aim at a uniform pooled analysis of the wealth of ovarian cancer array data already available. This will enhance the power of each separate ovarian cancer study and can lead to promising results.

[1]  J. Massagué,et al.  The logic of TGFβ signaling , 2006 .

[2]  E. Berns,et al.  TP53 and ovarian cancer , 2003, Human mutation.

[3]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[4]  J. Ferlay,et al.  Global Cancer Statistics, 2002 , 2005, CA: a cancer journal for clinicians.

[5]  Anil K Sood,et al.  Early events in the pathogenesis of epithelial ovarian cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  F. Slack,et al.  let-7 microRNAs in development, stem cells and cancer. , 2008, Trends in molecular medicine.

[7]  Tak-Hong Cheung,et al.  Prediction of chemotherapeutic response in ovarian cancer with DNA microarray expression profiling. , 2004, Cancer genetics and cytogenetics.

[8]  Dong Wang,et al.  Cellular processing of platinum anticancer drugs , 2005, Nature Reviews Drug Discovery.

[9]  R. Ochs,et al.  Genome-wide transcriptional analysis of carboplatin response in chemosensitive and chemoresistant ovarian cancer cells , 2005, Molecular Cancer Therapeutics.

[10]  A. Addario,et al.  Role of microRNAs in drug-resistant ovarian cancer cells. , 2008, Gynecologic oncology.

[11]  S. Kaye,et al.  Ovarian cancer: progress and continuing controversies in management. , 2002, European journal of cancer.

[12]  Bernard Têtu,et al.  Gene expression patterns of chemoresistant and chemosensitive serous epithelial ovarian tumors with possible predictive value in response to initial chemotherapy. , 2006, International journal of oncology.

[13]  S. Cannistra.  Cancer of the ovary. , 1993, The New England journal of medicine.

[14]  A. Mercurio,et al.  Tumor necrosis factor-alpha stimulates the epithelial-to-mesenchymal transition of human colonic organoids. , 2003, Molecular biology of the cell.

[15]  M. Buyse,et al.  The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. Gynecological Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer. , 1995, The New England journal of medicine.

[16]  S. Rosenwald,et al.  Tumor microRNA expression patterns associated with resistance to platinum based chemotherapy and survival in ovarian cancer patients. , 2009, Gynecologic oncology.

[17]  Javed Khan,et al.  Gene Expression Profiles Associated with Response to Chemotherapy in Epithelial Ovarian Cancers , 2005, Clinical Cancer Research.

[18]  Robert C. Bast,et al.  The biology of ovarian cancer: new opportunities for translation , 2009, Nature Reviews Cancer.

[19]  S. Cannistra,et al.  Gene-expression profiling in epithelial ovarian cancer , 2008, Nature Clinical Practice Oncology.

[20]  H. Dressman,et al.  MicroRNAs and their target messenger RNAs associated with ovarian cancer response to chemotherapy. , 2009, Gynecologic oncology.

[21]  J. Lieberman,et al.  let-7 Regulates Self Renewal and Tumorigenicity of Breast Cancer Cells , 2007, Cell.

[22]  Joel Greshock,et al.  MicroRNA microarray identifies Let-7i as a novel biomarker and therapeutic target in human epithelial ovarian cancer. , 2008, Cancer research.

[23]  J. Massagué,et al.  The logic of TGFbeta signaling. , 2006, FEBS letters.

[24]  W. Dalton,et al.  Mechanisms Associated with cell Adhesion Mediated Drug Resistance (CAM-DR) in Hematopoietic Malignancies , 2004, Cancer and Metastasis Reviews.

[25]  Maurice P H M Jansen,et al.  Molecular profiling of platinum resistant ovarian cancer , 2006, International journal of cancer.

[26]  Christopher Haslett,et al.  Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: A mechanism for small cell lung cancer growth and drug resistance in vivo , 1999, Nature Medicine.

[27]  Jacqueline A. Hall,et al.  Critical evaluation of p53 as a prognostic marker in ovarian cancer , 2004, Expert Reviews in Molecular Medicine.

[28]  Anil Potti,et al.  An integrated genomic-based approach to individualized treatment of patients with advanced-stage ovarian cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  P. Gunaratne.  Embryonic stem cell microRNAs: defining factors in induced pluripotent (iPS) and cancer (CSC) stem cells? , 2009, Current stem cell research & therapy.

[30]  M. Gore,et al.  Part I: chemotherapy for epithelial ovarian cancer-treatment at first diagnosis. , 2002, The Lancet. Oncology.

[31]  K. Nephew,et al.  Integrated analysis of DNA methylation and gene expression reveals specific signaling pathways associated with platinum resistance in ovarian cancer. , 2009, BMC medical genomics.

[32]  Douglas A Levine,et al.  Unique gene expression profile based on pathologic response in epithelial ovarian cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  T. Libermann,et al.  Carboplatin-induced gene expression changes in vitro are prognostic of survival in epithelial ovarian cancer , 2008, BMC Medical Genomics.

[34]  A. Berchuck,et al.  Prognostic significance of p53 mutation and p53 overexpression in advanced epithelial ovarian cancer: a Gynecologic Oncology Group Study. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  K. Tsuchida,et al.  Tumor-Stroma Interaction of Human Pancreatic Cancer: Acquired Resistance to Anticancer Drugs and Proliferation Regulation Is Dependent on Extracellular Matrix Proteins , 2004, Pancreas.

[36]  P. Wong,et al.  Dual roles of Nrf2 in cancer. , 2008, Pharmacological research.

[37]  Kathryn A. O’Donnell,et al.  c-Myc-regulated microRNAs modulate E2F1 expression , 2005, Nature.

[38]  David I. Smith,et al.  Gene Expression Profiles Predict Early Relapse in Ovarian Cancer after Platinum-Paclitaxel Chemotherapy , 2005, Clinical Cancer Research.

[39]  Carsten Denkert,et al.  Hyperactivation of the insulin-like growth factor receptor I signaling pathway is an essential event for cisplatin resistance of ovarian cancer cells. , 2009, Cancer research.

[40]  S. Minkin,et al.  High-resolution mapping of genomic imbalance and identification of gene expression profiles associated with differential chemotherapy response in serous epithelial ovarian cancer. , 2005, Neoplasia.

[41]  Bonnie F. Sloane,et al.  Proteases, extracellular matrix, and cancer: a workshop of the path B study section. , 2004, The American journal of pathology.