Kris Ann P Schultz1, Anne K Harris2, Michael Finch3, Louis P Dehner4, Jubilee B Brown5, David M Gershenson6, Robert H Young7, Amanda Field8, Weiying Yu9, Joyce Turner10, Nicholas G Cost11, Dominik T Schneider12, Douglas R Stewart13, A Lindsay Frazier14, Yoav Messinger2, D Ashley Hill15. 1. International Ovarian and Testicular Stromal Tumor Registry, Children's Minnesota, Minneapolis, MN, United States; Cancer and Blood Disorders, Children's Minnesota, Minneapolis, MN, United States. Electronic address: krisann.schultz@childrensmn.org. 2. International Ovarian and Testicular Stromal Tumor Registry, Children's Minnesota, Minneapolis, MN, United States; Cancer and Blood Disorders, Children's Minnesota, Minneapolis, MN, United States. 3. Children's Minnesota Research Institute, Children's Minnesota, Minneapolis, MN, United States. 4. International Ovarian and Testicular Stromal Tumor Registry, Children's Minnesota, Minneapolis, MN, United States; Lauren V. Ackerman Division of Surgical Pathology, Washington University Medical Center, St. Louis, MO, United States. 5. Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, United States. 6. Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, United States. 7. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States. 8. Department of Pathology and Center for Cancer & Immunology Research, Children's National Medical Center, Washington, DC, 20010, United States; Center for Genetic Medicine Research, Children's Research Institute, United States. 9. Department of Pathology and Center for Cancer & Immunology Research, Children's National Medical Center, Washington, DC, 20010, United States. 10. Division of Genetics, Children's National Medical Center, George Washington University School of Medicine & Health Sciences, Washington, DC, United States. 11. International Ovarian and Testicular Stromal Tumor Registry, Children's Minnesota, Minneapolis, MN, United States; Department of Surgery, Division of Urology, University of Colorado School of Medicine, Aurora, CO, United States. 12. Clinic of Pediatrics, Dortmund, Germany. 13. Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD. 14. International Ovarian and Testicular Stromal Tumor Registry, Children's Minnesota, Minneapolis, MN, United States; Dana-Farber Cancer Institute/Children's Cancer and Blood Disorders Center, Boston, MA, United States. 15. International Ovarian and Testicular Stromal Tumor Registry, Children's Minnesota, Minneapolis, MN, United States; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
Abstract
BACKGROUND: Ovarian sex cord-stromal tumors (OSCST) include juvenile granulosa cell tumors (JGCT), Sertoli-Leydig cell tumor (SLCT) and gynandroblastoma (GAB) among others. These ovarian sex cord-stromal tumors as well as other tumors including pleuropulmonary blastoma (PPB) may be associated with DICER1 mutations. We sought to describe the clinical and genetic findings from the first 107 individuals enrolled in the International Ovarian and Testicular Stromal Tumor Registry. METHODS: Medical and family history were obtained for individuals consecutively enrolled in the International Ovarian and Testicular Stromal Tumor Registry. Pathology was centrally reviewed. DICER1 sequencing was performed on blood and tumor tissue. RESULTS: Of the 107 participants, 49 had SLCT, 25 had JGCT and 5 had GAB. Nearly all (36/37) SLCTs and 4/4 GAB tested had a DICER1 mutation in an RNase IIIb domain hotspot; approximately half of these individuals had a predisposing germline DICER1 mutation. Metachronous SLCTs were seen in 3 individuals with germline DICER1 mutations. Other DICER1-associated conditions were seen in 19% of patients with SLCT or GAB. Three children of women with SLCT were diagnosed with PPB based on genetic testing and clinical screening during the course of this study. All were diagnosed with PPB in its earliest and most curable form (Type I), were treated with surgery alone, and are alive without evidence of disease. CONCLUSIONS: Recognition of the distinct genetic basis for a group of these tumors improves precise classification in difficult cases and promotes mutation-based screening and early detection.
BACKGROUND:Ovarian sex cord-stromal tumors (OSCST) include juvenile granulosa cell tumors (JGCT), Sertoli-Leydig cell tumor (SLCT) and gynandroblastoma (GAB) among others. These ovarian sex cord-stromal tumors as well as other tumors including pleuropulmonary blastoma (PPB) may be associated with DICER1 mutations. We sought to describe the clinical and genetic findings from the first 107 individuals enrolled in the International Ovarian and Testicular Stromal Tumor Registry. METHODS: Medical and family history were obtained for individuals consecutively enrolled in the International Ovarian and Testicular Stromal Tumor Registry. Pathology was centrally reviewed. DICER1 sequencing was performed on blood and tumor tissue. RESULTS: Of the 107 participants, 49 had SLCT, 25 had JGCT and 5 had GAB. Nearly all (36/37) SLCTs and 4/4 GAB tested had a DICER1 mutation in an RNase IIIb domain hotspot; approximately half of these individuals had a predisposing germline DICER1 mutation. Metachronous SLCTs were seen in 3 individuals with germline DICER1 mutations. Other DICER1-associated conditions were seen in 19% of patients with SLCT or GAB. Three children of women with SLCT were diagnosed with PPB based on genetic testing and clinical screening during the course of this study. All were diagnosed with PPB in its earliest and most curable form (Type I), were treated with surgery alone, and are alive without evidence of disease. CONCLUSIONS: Recognition of the distinct genetic basis for a group of these tumors improves precise classification in difficult cases and promotes mutation-based screening and early detection.
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