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 5) and the responders (n 5 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 5 0.09, p 5 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. ' 2005 Wiley-Liss, Inc.

Searching for potential biomarkers of cisplatin resistance in human ovarian cancer using a label‐free LC/MS‐based protein quantification method

“…In our study, we found a key DNA replication/ repair factor, proliferating cell nuclear antigen (PCNA) to be overexpressed in the cisplatin-resistant cell lines. Over the years, PCNA has been known to be involved in a broad base of metabolic pathways including DNA repair, and its overexpression is often found in drug-resistant cancer cell lines [37][38][39][40]. Overexpression of this protein in a resistant cell line suggests enhanced DNA repair activity which would inhibit cisplatin from causing cell death through cisplatin-DNA adduct formations.…”

Immunohistochemical analysis of possible chemoresistance markers identified by micro-arrays on serous ovarian carcinomas

“…Until now, very few markers were found to predict tumor response to chemotherapy and prognosis in ovarian cancer. [5][6][7] Recent advances in microarray technology led to identification of gene signatures that can help to improve diagnosis of ovarian cancer 8 and in vitro drug resistance 9,10 but not clinical response to chemotherapy. 11 We recently analyzed the gene expression patterns in advanced (FIGO stages III and IV) primary serous papillary carcinomas of the ovary displaying different response to first line chemotherapy in an attempt to identify specific molecular signatures associated with clinical response to chemotherapy.…”

Profiling Studies in Ovarian Cancer: A Review

“…Combining both profiles yielded better prognostic discrimination than either profile alone. Helleman et al [13] identified a nine-gene profile using microarray and reverse transcription-polymerase chain reaction (RT-PCR) that was able to classify tumors from 24 patients according to their response to platinum-based therapy. Using RT-PCR, this nine-gene set predicted platinum resistance in an independent validation set of 72 patients.…”