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.

Department of Gynaecologic Oncology Medical University Vienna General Hospital Vienna Spitalgasse 23 1090 Vienna Austria

Department of Gynecology and Obstetrics Kliniken Essen Mitte Henricistrasse 92 45136 Essen Germany

Department of Gynecology and Obstetrics University of Munich Marchioninistrasse 15 81377 Munich Germany

Department of Gynecology The Juliane Marie Centre Rigshospitalet Copenhagen University Hospital Blegdamsvej 9 DK 2100 Copenhagen Denmark

Department of Obstetrics and Gynecology Charité Universitätsmedizin Berlin Agustenburger Platz 1 13353 Berlin Germany

Department of Obstetrics and Gynecology Haukeland University Hospital Jonas Lies vei 72 5058 Bergen Norway

Department of Obstetrics and Gynecology University Hospitals Leuven Herestraat 49 3000 Leuven Belgium

Department of Obstetrics and Gynecology University Hospitals Leuven Leuven Belgium; Department of Obstetrics and Gynecology Innsbruck Medical University Anichstrasse 35 6020 Innsbruck Austria

Department of Obstetrics and Gynecology University Hospitals Leuven Leuven Belgium; Division of Gynaecological Oncology Leuven Cancer Institute Kuleuven Herestraat 49 3000 Leuven Belgium

Department of Pathology and Laboratory Diagnostics Maria Sklodowska Curie Institute Oncology Center Roentena 5 02 781 Warsaw Poland

Department of Pathology Herlev University Hospital Herlev Ringvej 75 DK 2730 Herlev Denmark

Department of Pathology University Hospitals Leuven Herestraat 49 3000 Leuven Belgium

Division of Clinical Therapeutics Oncology Department National and Kapodistrian Univerity of Athens 80 Vas Sofias Ave 11528 Athens Greece

Gynecologic Oncology Center Department of Obstetrics and Gynecology 1st Faculty of Medicine Charles University Prague General University Hospital Prague Ovocny trh 5 Prague 1 116 36 Czech Republic

Laboratory for Translational Genetics Department of Oncology KU Leuven Belgium; Center for Cancer Biology VIB Herestraat 49 bus 912 3000 Leuven Belgium

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

Pathology Department Vall d'Hebron University Hospital P Vall d'Hebron 119 129 08035 Barcelona Spain

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