Uterine leiomyosarcomas (uLMS) are rare, aggressive malignancies for which limited treatment options are available. To gain novel molecular insights into uLMS and identify potential novel therapeutic targets, we characterized 84 uLMS samples for genome-wide somatic copy number alterations, mutations, gene fusions and gene expression and performed a data integration analysis. We found that alterations affecting TP53, RB1, PTEN, MED12, YWHAE and VIPR2 were present in the majority of uLMS. Pathway analyses additionally revealed that the PI3K/AKT/mTOR, estrogen-mediated S-phase entry and DNA damage response signaling pathways, for which inhibitors have already been developed and approved, frequently harbored genetic changes. Furthermore, a significant proportion of uLMS was characterized by amplifications and overexpression of known oncogenes (CCNE1, TDO2), as well as deletions and reduced expression of tumor suppressor genes (PTEN, PRDM16). Overall, it emerged that the most frequently affected gene in our uLMS samples was VIPR2 (96%). Interestingly, VIPR2 deletion also correlated with unfavorable survival in uLMS patients (multivariate analysis; HR = 4.5, CI = 1.4-14.3, p = 1.2E-02), while VIPR2 protein expression was reduced in uLMS vs. normal myometrium. Moreover, stimulation of VIPR2 with its natural agonist VIP decreased SK-UT-1 uLMS cell proliferation in a dose-dependent manner. These data suggest that VIPR2, which is a negative regulator of smooth muscle cell proliferation, might be a novel tumor suppressor gene in uLMS. Our work further highlights the importance of integrative molecular analyses, through which we were able to uncover the genes and pathways most frequently affected by somatic alterations in uLMS.

Biomedical Research Group in Gynecology Vall Hebron Research Institute Universitat Autònoma de Barcelona CIBERONC Barcelona Spain

Centre for Gynecologic Oncology Amsterdam Antoni Van Leeuwenhoek Netherlands Cancer Institute Amsterdam The Netherlands

Department of Biopathology Institut Bergonié Bordeaux F 33000 France

Department of Obstetrics and Gynecology Gynecological Oncology Center Charles University Prague 1st Faculty of Medicine and General University Hospital Prague Prague Czech Republic

Department of Oncology Gynecologic Oncology KU Leuven Leuven 3000 Belgium

Department of Pathology and Genome Scale Research Program University of Helsinki and HUSLAB Helsinki University Hospital Helsinki Finland

Department of Pathology University of Turku and Turku University Hospital Turku Finland

Department of Pathology UZ Leuven KU Leuven Leuven B 3000 Belgium

Gynecological Oncology Department Vall Hebron University Hospital Barcelona Spain

Laboratory for Translational Genetics Department of Human Genetics KU Leuven Leuven Belgium

Pathological Oncology Group and Pathology Department Hospital U Arnau de Vilanova and Hospital U de Bellvitge IRBLLEIDA and Idibell University of Lleida CIBERONC Lleida Spain

VIB Center for Cancer Biology VIB Leuven Belgium

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