Abstract
ObjectiveThe first-line chemotherapy for ovarian cancer is based on a combination of platinum and taxane. To date, no reliable predictive biomarker has been recognized that is capable of identifying patients with pre-existing resistance to these agents. Here, we have established an integrated database and identified the most significant biomarker candidates for chemotherapy resistance in serous ovarian cancer. MethodsGene arrays were collected from the GEO and TCGA repositories. Treatment response was defined based on pathological response or duration of relapse-free survival. The responder and nonresponder cohorts were compared using the Mann-Whitney and receiver operating characteristic tests. An independent validation set was established to investigate the correlation between chemotherapy response for the top 8 genes. Statistical significance was set at p < 0.05. ResultsThe entire database included 1816 tumor samples from 12 independent datasets. From analyzing all the genes for platinum + taxane response, we identified the eight strongest genes correlated to chemotherapy resistance: AKIP1 (p = 1.60E-08, AUC = 0.728), MARVELD1 (p = 2.70E-07, AUC = 0.712), AKIRIN2 (p = 2.60E-07, AUC = 0.704), CFL1 (p = 8.10E-08, AUC = 0.694), SERBP1 (p = 8.10E-07, AUC = 0.684), PDXK (p = 1.30E-04, AUC = 0.634), TFE3 (p = 7.90E-05, AUC = 0.631) and NCOR2 (p = 1.90E-03, AUC = 0.611). Of these, the independent validation confirmed TFE3 (p = 0.012, AUC = 0.718), NCOR2 (p = 0.048, AUC = 0.671), PDXK (p = 0.019, AUC = 0.702), AKIP1 (p = 0.002, AUC = 0.773), MARVELD1 (p = 0.044, AUC = 0.675) and AKIRIN2 (p = 0.042, AUC = 0.676). An online interface was set up to enable future validation and ranking of new biomarker candidates in an automated manner (www.rocplot.org/ovar). ConclusionsWe compiled a large integrated database with available treatment and response information and used this to uncover new biomarkers of chemotherapy response in serous ovarian cancer.
Highlights
From analyzing all the genes for platinum + taxane response, we identified the eight strongest genes correlated to chemotherapy resistance: A-kinase interacting protein 1 (AKIP1) (p = 1.60E-08, area under the curve (AUC) = 0.728), MARVELD1 (p = 2.70E-07, AUC = 0.712), Akirin 2 (AKIRIN2) (p = 2.60E-07, AUC = 0.704), CFL1 (p = 8.10E-08, AUC = 0.694), SERBP1 (p = 8.10E-07, AUC = 0.684), Pyridoxal kinase (PDXK) (p = 1.30E-04, AUC = 0.634), transcription factor E3 (TFE3) (p = 7.90E-05, AUC = 0.631) and nuclear receptor corepressor 2 (NCOR2) (p = 1.90E-03, AUC = 0.611)
The recommendations of The National Comprehensive Cancer Network (NCCN) for advanced ovarian cancer treatment comprise surgery followed by systemic chemotherapy using cisplatin/paclitaxel
More than 80% of the patients initially respond to first-line treatment, most will have a recurrence within two years that progresses to advanced disease [4]
Summary
J.T. Fekete et al / Gynecologic Oncology 156 (2020) 654–661 disease vary by region and have shown an increasing trend in developed countries in the last decade [2]. Almost 90% of ovarian malignancies are of epithelial origin. From a histopathological point of view, epithelial ovarian cancer (EOC) can be divided into serous, endometroid, mucinous and clear-cell histology subtypes. Diagnosis of ovarian cancer is difficult because most patients are asymptomatic in the early stages, and many tumors are detected only in the advanced stages. The recommendations of The National Comprehensive Cancer Network (NCCN) for advanced ovarian cancer treatment comprise surgery followed by systemic chemotherapy using cisplatin/paclitaxel (www.nccn.org). More than 80% of the patients initially respond to first-line treatment, most will have a recurrence within two years that progresses to advanced disease [4]
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