Els Van Nieuwenhuysen1, Pieter Busschaert2, Patrick Neven3, Sileny N Han4, Philippe Moerman5, Michalis Liontos6, Maria Papaspirou6, Jolanta Kupryjanczyk7, Claus Hogdall8, Estrid Hogdall9, Ana Oaknin10, Angel Garcia11, Sven Mahner12, Fabian Trillsch13, David Cibula14, Florian Heitz15, Nicole Concin16, Paul Speiser17, Helga Salvesen18, Jalid Sehouli19, Diether Lambrechts20, Ignace Vergote21. 1. Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium; Division of Gynaecological Oncology, Leuven Cancer Institute, Kuleuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address: Els.vannieuwenhuysen@uzleuven.be. 2. Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Belgium; Center for Cancer Biology, VIB, Herestraat 49, bus 912, 3000 Leuven, Belgium. Electronic address: Pieter.busschaert@kuleuven.be. 3. Department of Obstetrics and Gynecology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address: Patrick.neven@uzleuven.be. 4. Department of Obstetrics and Gynecology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address: Sileny.han@uzleuven.be. 5. Department of Pathology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address: Philippe.Moerman@uzleuven.be. 6. Division of Clinical Therapeutics, Oncology Department, National and Kapodistrian Univerity of Athens, 80 Vas Sofias Ave, 11528 Athens, Greece. 7. Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Institute - Oncology Center, Roentena 5, 02-781 Warsaw, Poland. Electronic address: jkupry@coi.waw.pl. 8. Department of Gynecology, The Juliane Marie Centre, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Electronic address: Claus.hoegdall@regionh.dk. 9. Department of Pathology, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark. Electronic address: Estrid.hoegdall@regionh.dk. 10. Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain; Vall d'Hebron Institute of Oncology, VHIO, P. Vall d'Hebron 119-129, 08035 Barcelona, Spain. Electronic address: aoaknin@vhio.net. 11. Pathology Department, Vall d'Hebron University Hospital, P. Vall d'Hebron 119-129, 08035 Barcelona, Spain. Electronic address: agarcia@vhebron.net. 12. Department of Gynecology and Obstetrics, University of Munich, Marchioninistrasse 15, 81377 Munich, Germany. Electronic address: Sven.Mahner@med.uni-muenchen.de. 13. Department of Gynecology and Obstetrics, University of Munich, Marchioninistrasse 15, 81377 Munich, Germany. Electronic address: Fabian.Trillsch@med.uni-muenchen.de. 14. Gynecologic Oncology Center, Department of Obstetrics and Gynecology, First Faculty of Medicine, Charles University in Prague, General University Hospital in Prague, Ovocny trh 5, Prague 1 116 36, Czech Republic. Electronic address: dc@davidcibula.cz. 15. Department of Gynecology and Obstetrics, Kliniken Essen Mitte, Henricistrasse 92, 45136 Essen, Germany. Electronic address: F.Heitz@kliniken-essen-mitte.de. 16. Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium; Department of Obstetrics and Gynecology, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria. Electronic address: Nicole.concin@i-med.ac.at. 17. Department of Gynaecologic Oncology, Medical University Vienna, General Hospital Vienna, Spitalgasse 23, 1090 Vienna, Austria. 18. Department of Obstetrics and Gynecology, Haukeland University Hospital, Jonas Lies vei 72, 5058 Bergen, Norway. 19. Department of Obstetrics and Gynecology, Charité Universitätsmedizin Berlin, Agustenburger Platz 1, 13353 Berlin, Germany. Electronic address: Jalid.Sehouli@charite.de. 20. Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Belgium; Center for Cancer Biology, VIB, Herestraat 49, bus 912, 3000 Leuven, Belgium. Electronic address: Diether.lambrechts@kuleuven.vib.be. 21. Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium; Division of Gynaecological Oncology, Leuven Cancer Institute, Kuleuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address: Ignace.vergote@uzleuven.be.
Abstract
BACKGROUND: Ovarian germ cell tumors (OGCT) are rare gynecological neoplasms, mostly affecting children and young women. The underlying molecular genetic background of these tumors is poorly characterized. METHODS: We analyzed somatic copy number aberration (CNA) profiles in 87 OGCT tumors and performed whole exome sequencing (WES) on 24 OGCT tumor and matched germline samples to further elucidate their molecular genetic landscape. RESULTS: The overall mutation rate was very low in OGCT compared to other human cancers, with an average of 0.05 mutations per Mb, consistent with their embryological origin. We identified recurrent mutations in KIT and KRAS, while CNA profiling revealed frequent focal amplifications affecting PIK3CA and AKT1 in yolk sac tumors, recurrent focal deletions affecting chromosomal regions 1p36.32, 2q11.1, 4q28.1, 5p15.33, 5q11.1 and 6q27, as well as gains in chromosome 12p that were present in all tumors, except for pure immature teratomas. CONCLUSION: We here present the first whole exome sequencing data and to our knowledge the largest CNA study in OGCT. We confirmed that earlier reported KIT mutations were frequent in dysgerminomas and mixed forms with a dysgerminoma component, whereas chromosome 12p gains were present in all histological subtypes except pure immature teratomas. We detected recurrent KRAS mutations, recurrent focal deletions and an enrichment in the PI3K/AKT/PTEN pathway in yolk sac tumors. Several of these aberrations involve targetable pathways, offering novel treatment modalities for OGCT.
BACKGROUND:Ovarian germ cell tumors (OGCT) are rare gynecological neoplasms, mostly affecting children and young women. The underlying molecular genetic background of these tumors is poorly characterized. METHODS: We analyzed somatic copy number aberration (CNA) profiles in 87 OGCT tumors and performed whole exome sequencing (WES) on 24 OGCT tumor and matched germline samples to further elucidate their molecular genetic landscape. RESULTS: The overall mutation rate was very low in OGCT compared to other humancancers, with an average of 0.05 mutations per Mb, consistent with their embryological origin. We identified recurrent mutations in KIT and KRAS, while CNA profiling revealed frequent focal amplifications affecting PIK3CA and AKT1 in yolk sac tumors, recurrent focal deletions affecting chromosomal regions 1p36.32, 2q11.1, 4q28.1, 5p15.33, 5q11.1 and 6q27, as well as gains in chromosome 12p that were present in all tumors, except for pure immature teratomas. CONCLUSION: We here present the first whole exome sequencing data and to our knowledge the largest CNA study in OGCT. We confirmed that earlier reported KIT mutations were frequent in dysgerminomas and mixed forms with a dysgerminoma component, whereas chromosome 12p gains were present in all histological subtypes except pure immature teratomas. We detected recurrent KRAS mutations, recurrent focal deletions and an enrichment in the PI3K/AKT/PTEN pathway in yolk sac tumors. Several of these aberrations involve targetable pathways, offering novel treatment modalities for OGCT.
Authors: Douglas A Mata; Soo-Ryum Yang; Donna C Ferguson; Ying Liu; Rohit Sharma; Jamal K Benhamida; Hikmat A Al-Ahmadie; Debyani Chakravarty; David B Solit; Satish K Tickoo; Sounak Gupta; Maria E Arcila; Marc Ladanyi; Darren R Feldman; Victor E Reuter; Chad M Vanderbilt Journal: Urology Date: 2020-07-25 Impact factor: 2.649
Authors: C Newton; K Murali; A Ahmad; H Hockings; R Graham; V Liberale; S-J Sarker; J Ledermann; D M Berney; J Shamash; S Banerjee; S Stoneham; M Lockley Journal: Eur J Cancer Date: 2019-04-04 Impact factor: 9.162
Authors: Thomas R W Oliver; Lia Chappell; Rashesh Sanghvi; Lauren Deighton; Naser Ansari-Pour; Stefan C Dentro; Matthew D Young; Tim H H Coorens; Hyunchul Jung; Tim Butler; Matthew D C Neville; Daniel Leongamornlert; Mathijs A Sanders; Yvette Hooks; Alex Cagan; Thomas J Mitchell; Isidro Cortes-Ciriano; Anne Y Warren; David C Wedge; Rakesh Heer; Nicholas Coleman; Matthew J Murray; Peter J Campbell; Raheleh Rahbari; Sam Behjati Journal: Nat Commun Date: 2022-08-11 Impact factor: 17.694
Authors: Asaf Maoz; Koji Matsuo; Marcia A Ciccone; Shinya Matsuzaki; Maximilian Klar; Lynda D Roman; Anil K Sood; David M Gershenson Journal: Cancers (Basel) Date: 2020-05-29 Impact factor: 6.639