Identification of the IGF1/PI3K/NF κB/ERK gene signalling networks associated with chemotherapy resistance and treatment response in high-grade serous epithelial ovarian cancer

BMC Cancer

Jeremy A Squire⁶  Paul C Park⁴  Harriet E Feilotter⁴  Kenneth Evans⁸  Moyez Dharsee⁸  Peter Bryson¹  Timothy Childs⁴  Johanne Weberpals⁵  Colleen Crane²  Alexandria Haslehurst⁴  Paulo Nuin⁸  Robert J Gooding³  Madhuri Koti⁷ 

[1]Department of Obstetrics and Gynecology, Queen’s University, Kingston, ON, Canada

[2]Department of Pathology, The Ottawa Hospital, Ottawa, ON, Canada

[3]Department of Physics, Engineering Physics and Astronomy, Queen’s University, Kingston, ON, Canada

[4]Department of Pathology and Molecular Medicine, Queen’s University, Kingston, ON, Canada

[5]Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, Canada

[6]Departments of Genetics and Pathology, Faculdade de Medicina de Ribeirão Preto, University of Sao Paulo, Brazil

[7]Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada

[8]Ontario Cancer Biomarker Network, Toronto, ON, Canada

关键词: Microarray;    Gene expression;    Biomarkers;    Chemotherapy resistance;    Ovarian cancer;   

Others  :  859249
DOI  :  10.1186/1471-2407-13-549

 received in 2013-07-17, accepted in 2013-10-31,  发布年份 2013

【 摘 要 】

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 standard platinum-based chemotherapy. Twelve patient tumours demonstrating relative resistance to platinum chemotherapy corresponding to shorter PFS (< eight months) were compared to sixteen tumours from platinum-sensitive patients (PFS > eighteen months). Whole transcriptome profiling was performed using an Affymetrix high-resolution microarray platform to permit global comparisons of gene expression profiles between tumours 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/NF κB/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. In addition, our results provide a pathway context for further experimental validations, and the findings are a significant step towards future therapeutic interventions.

【 授权许可】

   
2013 Koti et al.; licensee BioMed Central Ltd.

【 图 表 】

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