PURPOSE: To identify a biomarker of ovarian cancer response to chemotherapy. PATIENTS AND METHODS Study: participants had epithelial ovarian cancer treated with surgery followed by platinum-based chemotherapy. DNA and RNA were isolated from frozen tumors and normal DNA was isolated from matched peripheral blood. A whole-genome loss of heterozygosity (LOH) analysis was performed using a high-density oligonucleotide array. Candidate genomic areas that predicted enhanced response to chemotherapy were identified with Cox proportional hazards methods. Gene expression analyses were performed through microarray experiments. Candidate genes were tested for independent effects on survival using Cox proportional hazards models, Kaplan-Meier survival curves, and the log-rank test. RESULTS: Using a whole-genome approach to study the molecular determinants of ovarian cancer response to platinum-based chemotherapy, we identified LOH of a 13q region to predict prolonged progression-free survival (PFS; hazard ratio, 0.23; P = .006). ERCC5 was identified as a candidate gene in this region because of its known function in the nucleotide excision repair pathway, the unique DNA repair pathway that removes platinum-DNA adducts. We found LOH of the ERCC5 gene locus and downregulation of ERCC5 gene expression to predict prolonged PFS. Integration of genomic and gene expression data shows a correlation between 13q LOH and ERCC5 gene downregulation. CONCLUSION: ERCC5 is a novel biomarker of ovarian cancer prognosis and a potential therapeutic target of ovarian cancer response to platinum chemotherapy.
PURPOSE: To identify a biomarker of ovarian cancer response to chemotherapy. PATIENTS AND METHODS Study: participants had epithelial ovarian cancer treated with surgery followed by platinum-based chemotherapy. DNA and RNA were isolated from frozen tumors and normal DNA was isolated from matched peripheral blood. A whole-genome loss of heterozygosity (LOH) analysis was performed using a high-density oligonucleotide array. Candidate genomic areas that predicted enhanced response to chemotherapy were identified with Cox proportional hazards methods. Gene expression analyses were performed through microarray experiments. Candidate genes were tested for independent effects on survival using Cox proportional hazards models, Kaplan-Meier survival curves, and the log-rank test. RESULTS: Using a whole-genome approach to study the molecular determinants of ovarian cancer response to platinum-based chemotherapy, we identified LOH of a 13q region to predict prolonged progression-free survival (PFS; hazard ratio, 0.23; P = .006). ERCC5 was identified as a candidate gene in this region because of its known function in the nucleotide excision repair pathway, the unique DNA repair pathway that removes platinum-DNA adducts. We found LOH of the ERCC5 gene locus and downregulation of ERCC5 gene expression to predict prolonged PFS. Integration of genomic and gene expression data shows a correlation between 13q LOH and ERCC5 gene downregulation. CONCLUSION:ERCC5 is a novel biomarker of ovarian cancer prognosis and a potential therapeutic target of ovarian cancer response to platinum chemotherapy.
Authors: Warapen Treekitkarnmongkol; Hiroshi Katayama; Kazuharu Kai; Kaori Sasai; Jennifer Carter Jones; Jing Wang; Li Shen; Aysegul A Sahin; Mihai Gagea; Naoto T Ueno; Chad J Creighton; Subrata Sen Journal: Carcinogenesis Date: 2016-09-13 Impact factor: 4.944
Authors: Eliezer M Van Allen; Kent W Mouw; Philip Kim; Gopa Iyer; Nikhil Wagle; Hikmat Al-Ahmadie; Cong Zhu; Irina Ostrovnaya; Gregory V Kryukov; Kevin W O'Connor; John Sfakianos; Ilana Garcia-Grossman; Jaegil Kim; Elizabeth A Guancial; Richard Bambury; Samira Bahl; Namrata Gupta; Deborah Farlow; Angela Qu; Sabina Signoretti; Justine A Barletta; Victor Reuter; Jesse Boehm; Michael Lawrence; Gad Getz; Philip Kantoff; Bernard H Bochner; Toni K Choueiri; Dean F Bajorin; David B Solit; Stacey Gabriel; Alan D'Andrea; Levi A Garraway; Jonathan E Rosenberg Journal: Cancer Discov Date: 2014-08-05 Impact factor: 39.397
Authors: Zhigang C Wang; Nicolai Juul Birkbak; Aedín C Culhane; Ronny Drapkin; Aquila Fatima; Ruiyang Tian; Matthew Schwede; Kathryn Alsop; Kathryn E Daniels; Huiying Piao; Joyce Liu; Dariush Etemadmoghadam; Alexander Miron; Helga B Salvesen; Gillian Mitchell; Anna DeFazio; John Quackenbush; Ross S Berkowitz; J Dirk Iglehart; David D L Bowtell; Ursula A Matulonis Journal: Clin Cancer Res Date: 2012-08-21 Impact factor: 12.531