title: Molecular profiling of platinum resistant ovarian cancer.
abstract: The aim of this study is to discover a gene set that can predict resistance to platinum-based chemotherapy in ovarian cancer. The study was performed on 96 primary ovarian adenocarcinoma specimens from 2 hospitals all treated with platinum-based chemotherapy. In our search for genes, 24 specimens of the discovery set (5 nonresponders and 19 responders) were profiled in duplicate with 18K cDNA microarrays. Confirmation was done using quantitative RT-PCR on 72 independent specimens (9 nonresponders and 63 responders). Sixty-nine genes were differentially expressed between the nonresponders (n=5) and the responders (n=19) in the discovery phase. An algorithm was constructed to identify predictive genes in this discovery set. This resulted in 9 genes (FN1, TOP2A, LBR, ASS, COL3A1, STK6, SGPP1, ITGAE, PCNA), which were confirmed with qRT-PCR. This gene set predicted platinum resistance in an independent validation set of 72 tumours with a sensitivity of 89% (95% CI: 0.68-1.09) and a specificity of 59% (95% CI: 0.47-0.71)(OR=0.09, p=0.026). Multivariable analysis including patient and tumour characteristics demonstrated that this set of 9 genes is independent for the prediction of resistance (p<0.01). The findings of this study are the discovery of a gene signature that classifies the tumours, according to their response, and a 9-gene set that determines resistance in an independent validation set that outperforms patient and tumour characteristics. A larger independent multicentre study should further confirm whether this 9-gene set can identify the patients who will not respond to platinum-based chemotherapy and could benefit from other therapies.
authors.affiliation: Department of Medical Oncology, Erasmus MC/Daniel den Hoed Cancer Centre, Rotterdam, The Netherlands.
authors.forename: Jozien
authors.initials: J
authors.lastname: Helleman
authors.forename: Maurice P H M
authors.initials: MP
authors.lastname: Jansen
authors.forename: Paul N
authors.initials: PN
authors.lastname: Span
authors.forename: Iris L
authors.initials: IL
authors.lastname: van Staveren
authors.forename: Leon F A G
authors.initials: LF
authors.lastname: Massuger
authors.forename: Marion E
authors.initials: ME
authors.lastname: Meijer-van Gelder
authors.forename: Fred C G J
authors.initials: FC
authors.lastname: Sweep
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Ewing
authors.forename: Maria E L
authors.initials: ME
authors.lastname: van der Burg
authors.forename: Gerrit
authors.initials: G
authors.lastname: Stoter
authors.forename: Kees
authors.initials: K
authors.lastname: Nooter
authors.forename: Els M J J
authors.initials: EM
authors.lastname: Berns
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D011237:Predictive Value of Tests; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin