Jolijn W Groeneweg1, Joline F Roze2, Edith D J Peters3, Ferdinando Sereno3, Anna G J Brink2, Sterre T Paijens4, Hans W Nijman4, Hannah S van Meurs5, Luc R C W van Lonkhuijzen5, Jurgen M J Piek6, Christianne A R Lok7, Glen R Monroe2, Gijs W van Haaften3, Ronald P Zweemer2. 1. Department of Gynecologic Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. Electronic address: j.w.groeneweg-11@umcutrecht.nl. 2. Department of Gynecologic Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. 3. Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. 4. Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. 5. Department of Gynecologic Oncology, Center for Gynecologic Oncology Amsterdam, Amsterdam University Medical Center, Amsterdam, the Netherlands. 6. Department of Obstetrics and Gynecology, Catharina Hospital, Eindhoven, the Netherlands. 7. Department of Gynecologic Oncology, Center for Gynecologic Oncology Amsterdam, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
Abstract
OBJECTIVE: Adult granulosa cell tumors (aGCTs) represent a rare, hormonally active subtype of ovarian cancer that has a tendency to relapse late and repeatedly. Current serum hormone markers are inaccurate in reflecting tumor burden in a subset of aGCT patients, indicating the need for a novel biomarker. We investigated the presence of circulating tumor DNA (ctDNA) harboring a FOXL2 or TERT promoter mutation in serial plasma samples of aGCT patients to determine its clinical value for monitoring disease. METHODS: In a national multicenter study, plasma samples (n = 110) were prospectively collected from 21 patients with primary (n = 3) or recurrent (n = 18) aGCT harboring a FOXL2 402C > G and/or TERT (C228T or C250T) promoter mutation. Circulating cell-free DNA was extracted and assessed for ctDNA containing one of either mutations using droplet digital PCR (ddPCR). Fractional abundance of FOXL2 mutant and TERT mutant ctDNA was correlated with clinical parameters. RESULTS: FOXL2 mutant ctDNA was found in plasma of 11 out of 14 patients (78.6%) with aGCT with a confirmed FOXL2 mutation. TERT C228T or TERT C250T mutant ctDNA was detected in plasma of 4 of 10 (40%) and 1 of 2 patients, respectively. Both FOXL2 mutant ctDNA and TERT promoter mutant ctDNA levels correlated with disease progression and treatment response in the majority of patients. CONCLUSIONS: FOXL2 mutant ctDNA was present in the majority of aGCT patients and TERT promoter mutant ctDNA has been identified in a smaller subset of patients. Both FOXL2 and TERT mutant ctDNA detection may have clinical value in disease monitoring.
OBJECTIVE: Adult granulosa cell tumors (aGCTs) represent a rare, hormonally active subtype of ovarian cancer that has a tendency to relapse late and repeatedly. Current serum hormone markers are inaccurate in reflecting tumor burden in a subset of aGCT patients, indicating the need for a novel biomarker. We investigated the presence of circulating tumor DNA (ctDNA) harboring a FOXL2 or TERT promoter mutation in serial plasma samples of aGCT patients to determine its clinical value for monitoring disease. METHODS: In a national multicenter study, plasma samples (n = 110) were prospectively collected from 21 patients with primary (n = 3) or recurrent (n = 18) aGCT harboring a FOXL2 402C > G and/or TERT (C228T or C250T) promoter mutation. Circulating cell-free DNA was extracted and assessed for ctDNA containing one of either mutations using droplet digital PCR (ddPCR). Fractional abundance of FOXL2 mutant and TERT mutant ctDNA was correlated with clinical parameters. RESULTS: FOXL2 mutant ctDNA was found in plasma of 11 out of 14 patients (78.6%) with aGCT with a confirmed FOXL2 mutation. TERT C228T or TERT C250T mutant ctDNA was detected in plasma of 4 of 10 (40%) and 1 of 2 patients, respectively. Both FOXL2 mutant ctDNA and TERT promoter mutant ctDNA levels correlated with disease progression and treatment response in the majority of patients. CONCLUSIONS: FOXL2 mutant ctDNA was present in the majority of aGCT patients and TERT promoter mutant ctDNA has been identified in a smaller subset of patients. Both FOXL2 and TERT mutant ctDNA detection may have clinical value in disease monitoring.
Authors: Wissam Dahoud; Jesse Handler; Vamsi Parimi; Christian F Meyer; Stephanie L Wethington; James R Eshleman; Russell Vang; Brigitte M Ronnett; Deyin Xing Journal: Int J Gynecol Pathol Date: 2021-12-03 Impact factor: 3.326
Authors: Nan Ni; Xin Fang; Destiny A Mullens; James J Cai; Ivan Ivanov; Laurent Bartholin; Qinglei Li Journal: Cancers (Basel) Date: 2022-04-27 Impact factor: 6.575