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Open AccessArticle

Whole Genome Analysis of Ovarian Granulosa Cell Tumors Reveals Tumor Heterogeneity and a High-Grade TP53-Specific Subgroup

1
Department of Gynaecological Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands
2
Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Oncode Institute, Utrecht University, 3584 CX Utrecht, The Netherlands
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Department of Obstetrics and Gynaecology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
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Department of Gynecological Oncology, Centre for Gynaecological Oncology Amsterdam, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands
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Department of Obstetrics and Gynaecology, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands
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Department of Gynaecological Oncology, Centre for Gynaecological Oncology Amsterdam, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, The Netherlands
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Department of Pathology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands
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Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(5), 1308; https://doi.org/10.3390/cancers12051308
Received: 22 April 2020 / Revised: 14 May 2020 / Accepted: 19 May 2020 / Published: 21 May 2020
Adult granulosa cell tumors (AGCTs) harbor a somatic FOXL2 c.402C>G mutation in ~95% of cases and are mainly surgically removed due to limited systemic treatment effect. In this study, potentially targetable genomic alterations in AGCTs were investigated by whole genome sequencing on 46 tumor samples and matched normal DNA. Copy number variant (CNV) analysis confirmed gain of chromosome 12 and 14, and loss of 22. Pathogenic TP53 mutations were identified in three patients with highest tumor mutational burden and mitotic activity, defining a high-grade AGCT subgroup. Within-patient tumor comparisons showed 29–80% unique somatic mutations per sample, suggesting tumor heterogeneity. A higher mutational burden was found in recurrent tumors, as compared to primary AGCTs. FOXL2-wildtype AGCTs harbored DICER1, TERT(C228T) and TP53 mutations and similar CNV profiles as FOXL2-mutant tumors. Our study confirms that absence of the FOXL2 c.402C>G mutation does not exclude AGCT diagnosis. The lack of overlapping variants in targetable cancer genes indicates the need for personalized treatment for AGCT patients. View Full-Text
Keywords: whole genome sequencing; granulosa cell tumors; ovarian cancer; FOXL2; tumor heterogeneity whole genome sequencing; granulosa cell tumors; ovarian cancer; FOXL2; tumor heterogeneity
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Roze, J.; Monroe, G.; Kutzera, J.; Groeneweg, J.; Stelloo, E.; Paijens, S.; Nijman, H.; van Meurs, H.; van Lonkhuijzen, L.; Piek, J.; Lok, C.; Jonges, G.; Witteveen, P.; Verheijen, R.; van Haaften, G.; Zweemer, R. Whole Genome Analysis of Ovarian Granulosa Cell Tumors Reveals Tumor Heterogeneity and a High-Grade TP53-Specific Subgroup. Cancers 2020, 12, 1308.

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