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.


CONCLUSIONS
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.
Helleman
Jozien
J
Department of Medical Oncology, Erasmus MC-JNI-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands. j.helleman@erasmusmc.nl
Smid
Marcel
M
Jansen
Maurice P H M
MP
van der Burg
Maria E L
ME
Berns
Els M J J
EM
D000970:Antineoplastic Agents / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics*
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds