Adult‐type granulosa cell tumor of the ovary: a FOXL2‐centric disease
Abstract Adult‐type granulosa cell tumors (aGCTs) account for 90% of malignant ovarian sex cord‐stromal tumors and 2–5% of all ovarian cancers. These tumors are usually diagnosed at an early stage and are treated with surgery. However, one‐third of patients relapse between 4 and 8 years after initia...
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Format: | Article |
Language: | English |
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Wiley
2021-05-01
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Series: | The Journal of Pathology: Clinical Research |
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Online Access: | https://doi.org/10.1002/cjp2.198 |
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doaj-119bf70995b744d0addb4d02ce2fc2fa |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jessica A Pilsworth Dawn R Cochrane Samantha J Neilson Bahar H Moussavi Daniel Lai Aslı D Munzur Janine Senz Yi Kan Wang Sina Zareian Ali Bashashati Adele Wong Jacqueline Keul Annette Staebler Hannah S vanMeurs Hugo M Horlings Stefan Kommoss Friedrich Kommoss Esther Oliva Anniina EM Färkkilä Blake Gilks David G Huntsman |
spellingShingle |
Jessica A Pilsworth Dawn R Cochrane Samantha J Neilson Bahar H Moussavi Daniel Lai Aslı D Munzur Janine Senz Yi Kan Wang Sina Zareian Ali Bashashati Adele Wong Jacqueline Keul Annette Staebler Hannah S vanMeurs Hugo M Horlings Stefan Kommoss Friedrich Kommoss Esther Oliva Anniina EM Färkkilä Blake Gilks David G Huntsman Adult‐type granulosa cell tumor of the ovary: a FOXL2‐centric disease The Journal of Pathology: Clinical Research adult‐type granulosa cell tumor of the ovary FOXL2 TERT promoter KMT2D targeted sequencing mutation profiling |
author_facet |
Jessica A Pilsworth Dawn R Cochrane Samantha J Neilson Bahar H Moussavi Daniel Lai Aslı D Munzur Janine Senz Yi Kan Wang Sina Zareian Ali Bashashati Adele Wong Jacqueline Keul Annette Staebler Hannah S vanMeurs Hugo M Horlings Stefan Kommoss Friedrich Kommoss Esther Oliva Anniina EM Färkkilä Blake Gilks David G Huntsman |
author_sort |
Jessica A Pilsworth |
title |
Adult‐type granulosa cell tumor of the ovary: a FOXL2‐centric disease |
title_short |
Adult‐type granulosa cell tumor of the ovary: a FOXL2‐centric disease |
title_full |
Adult‐type granulosa cell tumor of the ovary: a FOXL2‐centric disease |
title_fullStr |
Adult‐type granulosa cell tumor of the ovary: a FOXL2‐centric disease |
title_full_unstemmed |
Adult‐type granulosa cell tumor of the ovary: a FOXL2‐centric disease |
title_sort |
adult‐type granulosa cell tumor of the ovary: a foxl2‐centric disease |
publisher |
Wiley |
series |
The Journal of Pathology: Clinical Research |
issn |
2056-4538 |
publishDate |
2021-05-01 |
description |
Abstract Adult‐type granulosa cell tumors (aGCTs) account for 90% of malignant ovarian sex cord‐stromal tumors and 2–5% of all ovarian cancers. These tumors are usually diagnosed at an early stage and are treated with surgery. However, one‐third of patients relapse between 4 and 8 years after initial diagnosis, and there are currently no effective treatments other than surgery for these relapsed patients. As the majority of aGCTs (>95%) harbor a somatic mutation in FOXL2 (c.C402G; p.C134W), the aim of this study was to identify genetic mutations besides FOXL2 C402G in aGCTs that could explain the clinical diversity of this disease. Whole‐genome sequencing of 10 aGCTs and their matched normal blood was performed to identify somatic mutations. From this analysis, a custom amplicon‐based panel was designed to sequence 39 genes of interest in a validation cohort of 83 aGCTs collected internationally. KMT2D inactivating mutations were present in 10 of 93 aGCTs (10.8%), and the frequency of these mutations was similar between primary and recurrent aGCTs. Inactivating mutations, including a splice site mutation in candidate tumor suppressor WNK2 and nonsense mutations in PIK3R1 and NLRC5, were identified at a low frequency in our cohort. Missense mutations were identified in cell cycle‐related genes TP53, CDKN2D, and CDK1. From these data, we conclude that aGCTs are comparatively a homogeneous group of tumors that arise from a limited set of genetic events and are characterized by the FOXL2 C402G mutation. Secondary mutations occur in a subset of patients but do not explain the diverse clinical behavior of this disease. As the FOXL2 C402G mutation remains the main driver of this disease, progress in the development of therapeutics for aGCT would likely come from understanding the functional consequences of the FOXL2 C402G mutation. |
topic |
adult‐type granulosa cell tumor of the ovary FOXL2 TERT promoter KMT2D targeted sequencing mutation profiling |
url |
https://doi.org/10.1002/cjp2.198 |
work_keys_str_mv |
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doaj-119bf70995b744d0addb4d02ce2fc2fa2021-04-26T10:28:14ZengWileyThe Journal of Pathology: Clinical Research2056-45382021-05-017324325210.1002/cjp2.198Adult‐type granulosa cell tumor of the ovary: a FOXL2‐centric diseaseJessica A Pilsworth0Dawn R Cochrane1Samantha J Neilson2Bahar H Moussavi3Daniel Lai4Aslı D Munzur5Janine Senz6Yi Kan Wang7Sina Zareian8Ali Bashashati9Adele Wong10Jacqueline Keul11Annette Staebler12Hannah S vanMeurs13Hugo M Horlings14Stefan Kommoss15Friedrich Kommoss16Esther Oliva17Anniina EM Färkkilä18Blake Gilks19David G Huntsman20Department of Molecular Oncology British Columbia Cancer Research Centre Vancouver BC CanadaDepartment of Molecular Oncology British Columbia Cancer Research Centre Vancouver BC CanadaDepartment of Molecular Oncology British Columbia Cancer Research Centre Vancouver BC CanadaDepartment of Molecular Oncology British Columbia Cancer Research Centre Vancouver BC CanadaDepartment of Molecular Oncology British Columbia Cancer Research Centre Vancouver BC CanadaDepartment of Molecular Oncology British Columbia Cancer Research Centre Vancouver BC CanadaDepartment of Molecular Oncology British Columbia Cancer Research Centre Vancouver BC CanadaDepartment of Molecular Oncology British Columbia Cancer Research Centre Vancouver BC CanadaDepartment of Molecular Oncology British Columbia Cancer Research Centre Vancouver BC CanadaDepartment of Pathology and Laboratory Medicine University of British Columbia Vancouver BC CanadaDepartment of Pathology Massachusetts General Hospital Boston MA USADepartment of Women's Health Tübingen University Hospital Tübingen GermanyInstitute of Pathology and Neuropathology Tübingen University Hospital Tübingen GermanyDepartment of Gynecology Center for Gynecologic Oncology Amsterdam, Academic Medical Center Amsterdam The NetherlandsDepartment of Pathology The Netherlands Cancer Institute – Antoni van Leeuwenhoek Amsterdam The NetherlandsDepartment of Women's Health Tübingen University Hospital Tübingen GermanyInstitute of Pathology, Medizin Campus Bodensee Friedrichshafen GermanyDepartment of Pathology Massachusetts General Hospital Boston MA USAResearch Program for Systems Oncology University of Helsinki and Helsinki University Hospital Helsinki FinlandDepartment of Pathology and Laboratory Medicine University of British Columbia Vancouver BC CanadaDepartment of Molecular Oncology British Columbia Cancer Research Centre Vancouver BC CanadaAbstract Adult‐type granulosa cell tumors (aGCTs) account for 90% of malignant ovarian sex cord‐stromal tumors and 2–5% of all ovarian cancers. These tumors are usually diagnosed at an early stage and are treated with surgery. However, one‐third of patients relapse between 4 and 8 years after initial diagnosis, and there are currently no effective treatments other than surgery for these relapsed patients. As the majority of aGCTs (>95%) harbor a somatic mutation in FOXL2 (c.C402G; p.C134W), the aim of this study was to identify genetic mutations besides FOXL2 C402G in aGCTs that could explain the clinical diversity of this disease. Whole‐genome sequencing of 10 aGCTs and their matched normal blood was performed to identify somatic mutations. From this analysis, a custom amplicon‐based panel was designed to sequence 39 genes of interest in a validation cohort of 83 aGCTs collected internationally. KMT2D inactivating mutations were present in 10 of 93 aGCTs (10.8%), and the frequency of these mutations was similar between primary and recurrent aGCTs. Inactivating mutations, including a splice site mutation in candidate tumor suppressor WNK2 and nonsense mutations in PIK3R1 and NLRC5, were identified at a low frequency in our cohort. Missense mutations were identified in cell cycle‐related genes TP53, CDKN2D, and CDK1. From these data, we conclude that aGCTs are comparatively a homogeneous group of tumors that arise from a limited set of genetic events and are characterized by the FOXL2 C402G mutation. Secondary mutations occur in a subset of patients but do not explain the diverse clinical behavior of this disease. As the FOXL2 C402G mutation remains the main driver of this disease, progress in the development of therapeutics for aGCT would likely come from understanding the functional consequences of the FOXL2 C402G mutation.https://doi.org/10.1002/cjp2.198adult‐type granulosa cell tumor of the ovaryFOXL2TERT promoterKMT2Dtargeted sequencingmutation profiling |