Evelyn Despierre1, Matthieu Moisse2, Betül Yesilyurt2, Jalid Sehouli3, Ioana Braicu3, Sven Mahner4, Dan Cacsire Castillo-Tong5, Robert Zeillinger5, Sandrina Lambrechts6, Karin Leunen6, Frédéric Amant6, Philippe Moerman7, Diether Lambrechts8, Ignace Vergote6. 1. Gynecologic Oncology, University Hospitals Leuven, Leuven, Belgium; Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium. Electronic address: evelyndespierre@gmail.com. 2. Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium; Vesalius Research Center, VIB, Leuven, Belgium. 3. Department of Gynecology, Campus Virchow-Klinikum, Charité University Hospital, European Competence Center for Ovarian Cancer Berlin, Germany. 4. Department of Gynecology, Hamburg-Eppendorf University Medical Center, University Cancer Center Hamburg-Eppendorf (UCCH), Germany. 5. Department of Obstetrics and Gynecology, Molecular Oncology Group, Comprehensive Cancer Center, Gynecologic Cancer Unit, Medical University of Vienna, Austria. 6. Gynecologic Oncology, University Hospitals Leuven, Leuven, Belgium; Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium. 7. Department of Pathology, University Hospitals Leuven, Leuven, Belgium. 8. Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium; Vesalius Research Center, VIB, Leuven, Belgium. Electronic address: Diether.Lambrechts@vib-kuleuven.be.
Abstract
OBJECTIVE: Platinum resistance remains an obstacle in the treatment of epithelial ovarian cancer (EOC). The goal of this study was to profile EOCs for somatic copy number alterations (SCNAs) as predictive markers of platinum response. METHODS: SCNAs were assessed in a discovery (n=86) and validation cohort (n=115) of high risk stage I or stage II-IV EOCs using high-resolution SNP arrays. ASCAT and GISTIC identified all significantly overrepresented amplified or deleted chromosomal regions. Cox regression and univariate analysis assessed which SCNAs correlated with overall survival (OS), progression-free survival (PFS), platinum-free interval (PFI) and platinum response. Relevant SCNAs were also assessed in a pooled analysis involving both cohorts and published SCNA data from The Cancer Genome Atlas (TCGA; n=227). RESULTS: We identified 53 regions to be significantly overrepresented in EOC. Of these, 6 were associated with OS, PFS or PFI in the discovery cohort at P<0.05. In the validation cohort, amplifications of chromosomal region 14q32.33, which contains AKT1 as a potential driver gene, also correlated with OS (OR=1.670; P=0.018). In a pooled analysis of 428 tumors, involving the discovery, validation and TCGA cohorts, 14q32.33 amplifications significantly reduced OS, PFS and PFI (HR=2.69, P=1.7×10(-4); HR=1.82, P=1.9×10(-2) and HR=1.80, P=2.2×10(-2) respectively). Moreover, AKT1 mRNA expression correlated with the number of chromosomal copies of the 14q32.33 region (P=2.8×10(-11);R(2)=0.26). CONCLUSIONS: We established that amplifications in 14q32.33 were associated with reduced OS, PFS, PFI and platinum resistance in three independent cohorts, suggesting that AKT1 amplifications act as a potentially predictive marker for EOC treated with platinum-based chemotherapy.
OBJECTIVE:Platinum resistance remains an obstacle in the treatment of epithelial ovarian cancer (EOC). The goal of this study was to profile EOCs for somatic copy number alterations (SCNAs) as predictive markers of platinum response. METHODS: SCNAs were assessed in a discovery (n=86) and validation cohort (n=115) of high risk stage I or stage II-IV EOCs using high-resolution SNP arrays. ASCAT and GISTIC identified all significantly overrepresented amplified or deleted chromosomal regions. Cox regression and univariate analysis assessed which SCNAs correlated with overall survival (OS), progression-free survival (PFS), platinum-free interval (PFI) and platinum response. Relevant SCNAs were also assessed in a pooled analysis involving both cohorts and published SCNA data from The Cancer Genome Atlas (TCGA; n=227). RESULTS: We identified 53 regions to be significantly overrepresented in EOC. Of these, 6 were associated with OS, PFS or PFI in the discovery cohort at P<0.05. In the validation cohort, amplifications of chromosomal region 14q32.33, which contains AKT1 as a potential driver gene, also correlated with OS (OR=1.670; P=0.018). In a pooled analysis of 428 tumors, involving the discovery, validation and TCGA cohorts, 14q32.33 amplifications significantly reduced OS, PFS and PFI (HR=2.69, P=1.7×10(-4); HR=1.82, P=1.9×10(-2) and HR=1.80, P=2.2×10(-2) respectively). Moreover, AKT1 mRNA expression correlated with the number of chromosomal copies of the 14q32.33 region (P=2.8×10(-11);R(2)=0.26). CONCLUSIONS: We established that amplifications in 14q32.33 were associated with reduced OS, PFS, PFI and platinum resistance in three independent cohorts, suggesting that AKT1 amplifications act as a potentially predictive marker for EOC treated with platinum-based chemotherapy.
Authors: Jamie P Kershner; Sean Yu McLoughlin; Juhan Kim; Andrew Morgenthaler; Christopher C Ebmeier; William M Old; Shelley D Copley Journal: J Bacteriol Date: 2016-09-22 Impact factor: 3.490
Authors: Lauren L Ritterhouse; Jonathan A Nowak; Kyle C Strickland; Elizabeth P Garcia; Yonghui Jia; Neal I Lindeman; Laura E Macconaill; Panagiotis A Konstantinopoulos; Ursula A Matulonis; Joyce Liu; Ross S Berkowitz; Marisa R Nucci; Christopher P Crum; Lynette M Sholl; Brooke E Howitt Journal: Mod Pathol Date: 2016-05-06 Impact factor: 7.842
Authors: Curtis B Hughesman; X J David Lu; Kelly Y P Liu; Yuqi Zhu; Catherine F Poh; Charles Haynes Journal: PLoS One Date: 2016-08-18 Impact factor: 3.240