Project description:Background: Resistance to platinum-based chemotherapy remains a major impediment in the treatment of serous epithelial ovarian cancer. The objective of this study was to use gene expression profiling to delineate major deregulated pathways and biomarkers associated with the development of intrinsic chemotherapy resistance upon exposure to standard first-line therapy for ovarian cancer. Methods: The study cohort comprised 28 patients divided into two groups based on their varying sensitivity to first-line chemotherapy using progression free survival (PFS) as a surrogate of response. All 28 patients had advanced stage, high-grade serous ovarian cancer, and were treated with the same standard platinum-based chemotherapy. Twelve patient tumors demonstrating relative resistance to platinum chemotherapy corresponding to shorter PFS (< eight months) were compared to sixteen tumors from platinum-sensitive patients (PFS > eighteen months). Whole transcriptome profiling was performed using a Affymetrix high-resolution microarray platform to permit global comparisons of gene expression profiles between tumors from the resistant group and the sensitive group. Results: Microarray data analysis revealed a set of 204 discriminating genes possessing expression levels, which could influence differential chemotherapy response between the two groups. Robust statistical testing was then performed which eliminated a dependence on the normalization algorithm employed, producing a restricted list of differentially regulated genes, and which found IGF1 to be the most strongly differentially expressed gene. Pathway analysis, based on the list of 204 genes, revealed enrichment in genes primarily involved in the IGF1/PI3K/NFκB/ERK gene signalling networks. Conclusions: This study has identified pathway specific prognostic biomarkers possibly underlying a differential chemotherapy response in patients undergoing standard platinum-based treatment of serous epithelial ovarian cancer. Future studies to validate these markers are necessary to apply this knowledge to biomarker-based clinical trials.

Project description:Changes in chromatin organization are associated with resistance to anti-cancer drugs, such as platinum-based chemotherapy used as the primary treatment of ovarian cancer. We have examined the genomic distribution of chromatin accessibility changes, and relationship to gene expression changes, occurring during acquisition of resistance in vivo of high grade serous ovarian cancer (HGSOC) patients and whether this associates with genomic DNA damage distribution. Using matched chemo-sensitive and chemo-resistant ovarian cell lines isolated from HGSOC patients before and following acquisition of clinical resistance to platinum-based chemotherapy, we have examined the relationship between chromatin accessibility by ATAC-seq, platinum-DNA adduct distribution by Pt-Exo-seq and gene expression by RNA-seq. We have correlated chromatin changes between the lines at gene promoters, CpG islands, enhancer sequences and other genomic regions with changes in gene expression and platinum-DNA adduct distribution. We observe chromatin conformation differences following acquisition of platinum-resistance, with the HGSOC resistant lines clustering together, separately from their respective sensitive counterparts. Resistant lines show altered chromatin accessibility at intergenic regions, but less so at gene promoters. Super-enhancers, as defined by clusters of cis-regulatory elements, at these intergenic regions show chromatin changes that are associated with altered expression of linked genes, with enrichment for genes involved in the Fanconi anemia/BRCA DNA damage response pathway. Genome-wide distribution of platinum adducts associates with the chromatin changes and distinguish sensitive from resistant lines. Regions incurring fewer platinum-adducts showed a significant reduction in accessibility the resistant HGSOC cell line PEO4 compared to the sensitive PEO1 counterpart. Surprisingly, regions showing increased damage in PEO4 had an even greater reduction in accessibility. In the resistant line, we observe fewer adducts around gene promoters and more adducts at intergenic regions. In cell lines derived from patients following acquisition of clinical resistance to platinum-based chemotherapy, chromatin changes at super-enhancers correlate with gene expression changes in DNA repair pathways known to influence platinum sensitivity. Although cisplatin is a relatively non-specific DNA damaging agent, there are consistent differences in distribution of adducts between the matched sensitive and resistant ovarian cell lines, which is independent of the overall level of adducts formed.

Project description:The presence of tumor cells in effusions within serosal cavities is a clinical manifestation of advanced-stage cancer and is generally associated with poor survival. Identifying molecular targets may help to design efficient treatments to eradicate these aggressive cancer cells and improve patient survival. Using a state-of-the-art Taqman-based qRT-PCR assay, we investigated the multidrug resistance (MDR) transcriptome of 32 unpaired ovarian serous carcinoma effusion samples obtained at diagnosis or at disease recurrence following chemotherapy. MDR genes were selected a priori based on an extensive curation of the literature published during the last three decades. We found three gene signatures with a statistically significant correlation with overall survival (OS), response to treatment (complete response - CR vs. other), and progression free survival (PFS). The median log-rank p-values for the signatures were 0.023, 0.034, and 0.008, respectively. No correlation was found with residual tumor status after cytoreductive surgery, treatment (with or without chemotherapy) and stage defined according to the International Federation of Gynecology and Obstetrics. Further analyses demonstrated that gene expression alone can effectively predict the survival outcome of women with ovarian serous carcinoma (OS: log-rank p=0.0000 and PFS: log-rank p=0.002). Interestingly, the signature for overall survival is the same in patients at first presentation and those who had chemotherapy and relapsed. This pilot study highlights two new gene signatures that may help in optimizing the treatment for ovarian carcinoma patients with effusions. In the study presented here, effusion samples were obtained from 32 patients diagnosed with serous ovarian carcinoma (n=25), primary peritoneal serous carcinoma (n=6) or tubal serous carcinoma (n=1). They were accrued at the Division of Pathology in the Norwegian Radium Hospital from 2000-2006. RNA was used to study the expression profile of 381 multidrug resistant-related genes.

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Gene expression data from high grade serous ovarian cancer

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