Eric J Devor1, Jeffrey Miecznikowski2, Brandon M Schickling3, Jesus Gonzalez-Bosquet4, Heather A Lankes5, Premal Thaker6, Peter A Argenta7, Michael L Pearl8, Susan L Zweizig9, Robert S Mannel10, Amy Brown11, Nilsa C Ramirez12, Olga B Ioffe13, Kay J Park14, William T Creasman15, Michael J Birrer16, David Mutch17, Kimberly K Leslie18. 1. Department of Obstetrics and Gynecology, University of Iowa Carver College of Medicine, United States; University of Iowa Hospitals and Clinics, Holden Comprehensive Cancer Center, United States. Electronic address: eric-devor@uiowa.edu. 2. Department of Biostatistics, SUNY University at Buffalo, United States. Electronic address: jcm38@buffalo.edu. 3. Department of Internal Medicine, University of Iowa Carver College of Medicine, United States. Electronic address: Brandon-schickling@uiowa.edu. 4. Department of Obstetrics and Gynecology, University of Iowa Carver College of Medicine, United States. Electronic address: jesus-gonzalezbosquet@uiowa.edu. 5. NRG Oncology Statistics and Data Management Center, Roswell Park Cancer Institute, United States. Electronic address: LankesH@NRGOncology.org. 6. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine and Siteman Cancer Center, St. Louis, MO, United States. Electronic address: thakerp@wudosis.wustl.edu. 7. University of Minnesota School of Medicine, Minneapolis, MN, United States. Electronic address: argenta@umn.edu. 8. Gynecologic Oncology, Stony Brook University Hospital, Stony Brook, NY, United States. Electronic address: Michael.Pearl@stonybrookmedicine.edu. 9. University of Massachusetts, United States. Electronic address: Susan.Zweizig@umassmemorial.org. 10. Gynecologic Oncology, Stephenson Oklahoma Cancer Center, Oklahoma City, OK, United States. Electronic address: robert-mannel@ouhsc.edu. 11. Department of Gynecology/Oncology, Hospital of Central Connecticut, New Britain, CT 06050, USA. Electronic address: abrown02@harthosp.org. 12. The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, United States. Electronic address: nilsa.ramirez@nationwidechildrens.org. 13. Department of Pathology, University of Maryland Medical Center, Baltimore, MD 21201, United States. Electronic address: oioffe@fpi.umaryland.edu. 14. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, United States. Electronic address: ParkK@MSKCC.ORG. 15. Medical University of South Carolina, USC Women's Health Gynecology, Charleston, SC 29425, United States. Electronic address: creasman@musc.edu. 16. Center for Cancer Research, The Gillette Center for Gynecologic Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States. Electronic address: MBIRRER@mgh.harvard.edu. 17. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine and Siteman Cancer Center, St. Louis, MO, United States. Electronic address: mutchd@wudosis.wustl.edu. 18. Department of Obstetrics and Gynecology, University of Iowa Carver College of Medicine, United States; University of Iowa Hospitals and Clinics, Holden Comprehensive Cancer Center, United States. Electronic address: kimberly-leslie@uiowa.edu.
Abstract
OBJECTIVE: Endometrial cancer can be diagnosed early and cured, yet cases that recur portend a very poor prognosis with over 10,000 women succumbing to the disease every year. In this study we addressed the question of how to recognize cases likely to recur early in the course of therapy using dysregulation of tumor microRNAs (miRNAs) as predictors. METHODS: Using the tissue collection from Gynecologic Oncology Group Study-210, we selected and analyzed expression of miRNAs in 54 recurrent and non-recurrent cases. The three most common histologic types, endometrioid adenocarcinoma (EEA), serous adenocarcinoma (ESA) and carcinosarcoma (UCS), were analyzed as three independent sets and their miRNA expression profiles compared. RESULTS: Only one miRNA was statistically different between recurrent and non-recurrent cases, and in only one histologic type: significant down-regulation of miR-181c was observed in EEA recurrence. Using several well-known databases to assess miR-181c targets, one target of particular relevance to cancer, NOTCH2, was well supported. Using The Cancer Genome Atlas and our validation tumor panel from the GOG-210 cohort, we confirmed that NOTCH2 is significantly over-expressed in EEA. In the most relevant endometrial adenocarcinoma cell model, Ishikawa H, altering miR-181c expression produces significant changes in NOTCH2 expression, consistent with direct targeting. CONCLUSIONS: Our findings suggest that increased NOTCH2 via loss of miR-181c is a significant component of EEA recurrence. This presents an opportunity to develop miR-181c and NOTCH2 as markers for early identification of high risk cases and the use of NOTCH inhibitors in the prevention or treatment of recurrent disease.
OBJECTIVE:Endometrial cancer can be diagnosed early and cured, yet cases that recur portend a very poor prognosis with over 10,000 women succumbing to the disease every year. In this study we addressed the question of how to recognize cases likely to recur early in the course of therapy using dysregulation of tumor microRNAs (miRNAs) as predictors. METHODS: Using the tissue collection from Gynecologic Oncology Group Study-210, we selected and analyzed expression of miRNAs in 54 recurrent and non-recurrent cases. The three most common histologic types, endometrioid adenocarcinoma (EEA), serous adenocarcinoma (ESA) and carcinosarcoma (UCS), were analyzed as three independent sets and their miRNA expression profiles compared. RESULTS: Only one miRNA was statistically different between recurrent and non-recurrent cases, and in only one histologic type: significant down-regulation of miR-181c was observed in EEA recurrence. Using several well-known databases to assess miR-181c targets, one target of particular relevance to cancer, NOTCH2, was well supported. Using The Cancer Genome Atlas and our validation tumor panel from the GOG-210 cohort, we confirmed that NOTCH2 is significantly over-expressed in EEA. In the most relevant endometrial adenocarcinoma cell model, Ishikawa H, altering miR-181c expression produces significant changes in NOTCH2 expression, consistent with direct targeting. CONCLUSIONS: Our findings suggest that increased NOTCH2 via loss of miR-181c is a significant component of EEA recurrence. This presents an opportunity to develop miR-181c and NOTCH2 as markers for early identification of high risk cases and the use of NOTCH inhibitors in the prevention or treatment of recurrent disease.
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