Sharareh Siamakpour-Reihani1, Lauren Patterson Cobb2, Chen Jiang3, Dadong Zhang4, Rebecca A Previs5, Kouros Owzar6, Andrew B Nixon7, Angeles Alvarez Secord8. 1. Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University Medical Center, United States. Electronic address: shara.reihani@duke.edu. 2. Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, United States. 3. Bioinformatics Shared Resource, Duke Cancer Institute, United States. Electronic address: Chen.X.Jiang@kp.org. 4. Bioinformatics Shared Resource, Duke Cancer Institute, United States. Electronic address: dadong.zhang@duke.edu. 5. Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, United States. Electronic address: rebecca.previs@duke.edu. 6. Duke Department of Biostatistics and Bioinformatics, Duke University Medical Center, United States; Bioinformatics Shared Resource, Duke Cancer Institute, United States. Electronic address: kouros.owzar@duke.edu. 7. Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University Medical Center, United States. Electronic address: andrew.nixon@duke.edu. 8. Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, United States. Electronic address: angeles.secord@duke.edu.
Abstract
OBJECTIVE: To identify novel immunologic targets and biomarkers associated with overall survival (OS) in high-grade serous ovarian cancer (HGSC). METHODS: In this retrospective study, microarray data from 51 HGSC specimens were analyzed (Affymetrix HG-U133A). A panel of 183 immune/inflammatory response related genes linked to 279 probe sets was constructed a priori and screened. Associations between gene expression and OS were assessed using logrank tests. Multiple testing was addressed within the False Discovery Rate (FDR) framework. For external validation, TCGA Ovarian dataset and five GSE publicly available HGSC datasets were evaluated. RESULTS: In Duke data, 110 probe sets linked to 83 immunologic/inflammatory-related genes were differentially expressed in tumors from long versus short-term HGSC survivors (adjusted p < 0.05). In TCGA, concordant with the results from the Duke discovery cohort, high expression of one probe (IL6R) demonstrated a consistent significance and concordant association with higher expression in long-term HGSC survivors (Duke q-value = 0.022) and improved OS in the TCGA dataset (p-value = 0.015, HR = 0.8). Thirteen genes in GSE14764 (N = 4) and GSE26712 (N = 9) datasets had significant p-values and consistent concordant with Duke Data. Despite the significant associations of gene expression and OS in the individual GSE datasets, in the GSE meta-analysis no genes were consistently concordant and significantly associated with survival. CONCLUSIONS: Evaluation of IL6R expression may be warranted based on higher expression in long-term survivors and association with improved survival in advanced HGSC. The other candidate genes may also be of worthy of further exploration to enhance immuno-oncology drug discovery.
OBJECTIVE: To identify novel immunologic targets and biomarkers associated with overall survival (OS) in high-grade serous ovarian cancer (HGSC). METHODS: In this retrospective study, microarray data from 51 HGSC specimens were analyzed (Affymetrix HG-U133A). A panel of 183 immune/inflammatory response related genes linked to 279 probe sets was constructed a priori and screened. Associations between gene expression and OS were assessed using logrank tests. Multiple testing was addressed within the False Discovery Rate (FDR) framework. For external validation, TCGA Ovarian dataset and five GSE publicly available HGSC datasets were evaluated. RESULTS: In Duke data, 110 probe sets linked to 83 immunologic/inflammatory-related genes were differentially expressed in tumors from long versus short-term HGSC survivors (adjusted p < 0.05). In TCGA, concordant with the results from the Duke discovery cohort, high expression of one probe (IL6R) demonstrated a consistent significance and concordant association with higher expression in long-term HGSC survivors (Duke q-value = 0.022) and improved OS in the TCGA dataset (p-value = 0.015, HR = 0.8). Thirteen genes in GSE14764 (N = 4) and GSE26712 (N = 9) datasets had significant p-values and consistent concordant with Duke Data. Despite the significant associations of gene expression and OS in the individual GSE datasets, in the GSE meta-analysis no genes were consistently concordant and significantly associated with survival. CONCLUSIONS: Evaluation of IL6R expression may be warranted based on higher expression in long-term survivors and association with improved survival in advanced HGSC. The other candidate genes may also be of worthy of further exploration to enhance immuno-oncology drug discovery.
Authors: F Stephen Hodi; Marcus Butler; Darryl A Oble; Michael V Seiden; Frank G Haluska; Andrea Kruse; Suzanne Macrae; Marybeth Nelson; Christine Canning; Israel Lowy; Alan Korman; David Lautz; Sara Russell; Michael T Jaklitsch; Nikhil Ramaiya; Teresa C Chen; Donna Neuberg; James P Allison; Martin C Mihm; Glenn Dranoff Journal: Proc Natl Acad Sci U S A Date: 2008-02-19 Impact factor: 11.205