Integrated genome analysis of uterine leiomyosarcoma to identify novel driver genes and targetable pathways

Abstract

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.

TDO2 Overexpression Is Associated with Cancer Stem Cells and Poor Prognosis in Esophageal Squamous Cell Carcinoma

“…Overexpression of TDO2 promoted tumor cell survival and was correlated with tumor grade and poor prognosis in triple negative breast cancer [18] and in brain tumors [19]. Furthermore, overexpression of TDO2 has been reported in human colorectal cancer and leiomyosarcoma [20,21]. However, the expression and biological significance of TDO2 in esophageal cancer have not been investigated.…”

Multifaceted Role of PRDM Proteins in Human Cancer

“…Otherwise, array-CGH integrated with gene expression analysis of leiomyosarcoma revealed a frequent loss at 1p36, which contains PRDM16, suggesting that this defect could promote muscle differentiation in this context [247]. Similarly, integrated analysis of uterine leiomyosarcoma revealed PRDM16 deletions and/or reduced expression [248]. In DNA array-CGH analysis of normal and sporadic colorectal cancer specimens, analyses of gains of focal minimal common regions also included PRDM16 among the candidate oncogenes of these malignancies [249].…”

Reasons to Reconsider Risk Associated With Power Morcellation of Uterine Fibroids

“…Recently, the results of genetic analyses have offered additional evidence for such a transformation. Regarding uterine leiomyosarcomas and STUMP, a subset of these shares genetic alterations occurring in fibroids, in particular mutations of MED12 (34)(35)(36)(37)(38)(39)(40)(41). This suggests an albeit very low probability of malignant transformation within pre-existing fibroids, in particular with cellular or symplastic areas (42) leading to STUMP and leiomyosarcomas.…”