TY - JOUR
T1 - Adult-type granulosa cell tumor of the ovary: a FOXL2-centric disease
AU - Pilsworth, Jessica A.
AU - Cochrane, Dawn R.
AU - Neilson, Samantha J.
AU - Moussavi, Bahar H.
AU - Lai, Daniel
AU - Munzur, Aslı D.
AU - Senz, Janine
AU - Wang, Yi Kan
AU - Zareian, Sina
AU - Bashashati, Ali
AU - Wong, Adele
AU - Keul, Jacqueline
AU - Staebler, Annette
AU - van Meurs, Hannah S.
AU - Horlings, Hugo M.
AU - Kommoss, Stefan
AU - Kommoss, Friedrich
AU - Oliva, Esther
AU - Färkkilä, Anniina E. M.
AU - Gilks, Blake
AU - Huntsman, David G.
N1 - Funding Information: We thank all the women who generously donated the samples used in this study. This work is supported by the Terry Fox Research Institute New Frontiers Program Project Grant #1082, the Canadian Institutes of Health Research Foundation Grant #154290, the BC Cancer Foundation, and the Vancouver General Hospital (VGH) & University of British Columbia (UBC) Hospital Foundation (to OVCARE: BC's Ovarian Cancer Research Team, Vancouver). JAP is supported by the University of British Columbia Four‐Year Doctoral Fellowship. DGH is supported by the Dr. Chew Wei Memorial Professorship in Gynecologic Oncology and the Canada Research Chairs Program (Research Chair in Molecular and Genomic Pathology). We are grateful to the clinicians from each institution for patient recruitment and the OVCARE Gynecologic Tissue bank for providing patient tissues. We also thank Drs. Blake Gilks, Friedrich Kommoss, Hugo M. Horlings, Ralf Butzow, Anthony N. Karnezis, Hector Li Chang, Basile Tessier‐Cloutier, and Lien Hoang for expert pathology review. We are grateful to Winnie Yang and Amy Lum for their technical support. Funding Information: We thank all the women who generously donated the samples used in this study. This work is supported by the Terry Fox Research Institute New Frontiers Program Project Grant #1082, the Canadian Institutes of Health Research Foundation Grant #154290, the BC Cancer Foundation, and the Vancouver General Hospital (VGH) & University of British Columbia (UBC) Hospital Foundation (to OVCARE: BC's Ovarian Cancer Research Team, Vancouver). JAP is supported by the University of British Columbia Four-Year Doctoral Fellowship. DGH is supported by the Dr. Chew Wei Memorial Professorship in Gynecologic Oncology and the Canada Research Chairs Program (Research Chair in Molecular and Genomic Pathology). We are grateful to the clinicians from each institution for patient recruitment and the OVCARE Gynecologic Tissue bank for providing patient tissues. We also thank Drs. Blake Gilks, Friedrich Kommoss, Hugo M. Horlings, Ralf Butzow, Anthony N. Karnezis, Hector Li Chang, Basile Tessier-Cloutier, and Lien Hoang for expert pathology review. We are grateful to Winnie Yang and Amy Lum for their technical support. Publisher Copyright: © 2021 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland & John Wiley & Sons, Ltd. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/5
Y1 - 2021/5
N2 - 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.
AB - 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.
KW - FOXL2
KW - KMT2D
KW - TERT promoter
KW - adult-type granulosa cell tumor of the ovary
KW - cell cycle genes
KW - mutation profiling
KW - ovarian cancer
KW - sex cord-stromal tumor
KW - targeted sequencing
UR - http://www.scopus.com/inward/record.url?scp=85099098070&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/cjp2.198
DO - https://doi.org/10.1002/cjp2.198
M3 - Article
C2 - 33428330
SN - 2056-4538
VL - 7
SP - 243
EP - 252
JO - journal of pathology. Clinical research
JF - journal of pathology. Clinical research
IS - 3
ER -