FOXL2 and TERT promoter mutation detection in circulating tumor DNA of adult granulosa cell tumors as biomarker for disease monitoring

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 in...

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Published in:	Gynecologic oncology Vol. 162; no. 2; pp. 413 - 420
Main Authors:	Groeneweg, Jolijn W., Roze, Joline F., Peters, Edith D.J., Sereno, Ferdinando, Brink, Anna G.J., Paijens, Sterre T., Nijman, Hans W., van Meurs, Hannah S., van Lonkhuijzen, Luc R.C.W., Piek, Jurgen M.J., Lok, Christianne A.R., Monroe, Glen R., van Haaften, Gijs W., Zweemer, Ronald P.
Format:	Journal Article
Language:	English
Published:	Elsevier Inc 01-08-2021
Subjects:	Biomarker ctDNA FOXL2 Granulosa cell tumor TERT Biomarker FOXL2 Granulosa cell tumor TERT ctDNA
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Summary:	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. 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. 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. 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. •CtDNA harboring a FOXL2 mutation was identified in plasma of 79% of patients with an adult granulosa cell tumor (aGCT).•CtDNA containing a TERT promoter mutation was detected in a smaller subset of included aGCT patients.•Both FOXL2 mutant ctDNA and TERT mutant ctDNA levels correlated with clinical disease activity in the majority of patients.•These findings suggest the clinical value of ctDNA detection as a biomarker for disease monitoring in aGCT.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-3 content type line 23 ObjectType-Undefined-2
ISSN:	0090-8258 1095-6859
DOI:	10.1016/j.ygyno.2021.05.027