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Integrated genome analysis of uterine leiomyosarcoma to identify novel driver genes and targetable pathways
Author(s) -
Cuppens Tine,
Moisse Matthieu,
Depreeuw Jeroen,
Annibali Daniela,
Colas Eva,
GilMoreno Antonio,
Huvila Jutta,
Carpén Olli,
Zikán Michal,
MatiasGuiu Xavier,
Moerman Philippe,
Croce Sabrina,
Lambrechts Diether,
Amant Frédéric
Publication year - 2017
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31129
Subject(s) - pten , biology , cancer research , pi3k/akt/mtor pathway , tumor suppressor gene , gene , signal transduction , genetics , carcinogenesis
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.