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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., (© 2017 UICC.)

Endometrial carcinomas, the most common malignant tumour of the female genital tract, are usually diagnosed at an early stage with uterine-confined disease and an overall favourable prognosis. However, up to 20% of endometrial carcinomas will end up in recurrent disease, associated with a drop in survival and representing the major clinical challenge. Management of this group of risk patients relies on robust biomarkers that may predict which endometrial carcinomas will relapse. For this, we performed a proteomic analysis comparing primary lesions with recurrences and identified ANXA2 as a potential biomarker associated with recurrent disease that we further validated in an independent series of samples by immunohistochemistry. We demonstrated in vitro a role for ANXA2 in the promotion of metastasis rather than interfering with sensitivity to radio/chemotherapy. In addition, ANXA2 silencing resulted in a reduced metastatic pattern in a mice model of endometrial cancer dissemination, with a limited presence of circulating tumor cells. Finally, a retrospective study in a cohort of 93 patients showed that ANXA2 effectively predicted those endometrioid endometrial carcinomas that finally recurred. Importantly, ANXA2 demonstrated a predictive value also among low risk Stage I endometrioid endometrial carcinomas, highlighting the clinical utility of ANXA2 biomarker as predictor of recurrent disease in endometrial cancer. Retrospective and prospective studies are ongoing to validate ANXA2 as a potential tool for optimal stratification of patients susceptible to receive radical surgery and radio/chemotherapy., (© 2014 UICC.)

Rapid and reliable diagnosis of endometrial cancer (EC) in uterine aspirates is highly desirable. Current sensitivity and failure rate of histological diagnosis limit the success of this method and subsequent hysteroscopy is often necessary. Using quantitative reverse transcriptase-polymerase chain reaction on RNA from uterine aspirates samples, we measured the expression level of 20 previously identified genes involved in EC pathology, created five algorithms based on combinations of five genes and evaluated their ability to diagnose EC. The algorithms were tested in a prospective, double-blind, multicenter study. We enlisted 514 patients who presented with abnormal uterine bleeding. EC was diagnosed in 60 of the 514 patients (12%). Molecular analysis was performed on the remnants of aspirates and results were compared to the final histological diagnoses obtained through biopsies acquired by aspiration or guided by hysteroscopy, or from the specimens resected by hysterectomy. Algorithm 5 was the best performing molecular diagnostic classifier in the case-control and validation study. The molecular test had a sensitivity of 81%, specificity of 96%, positive predictive value (PPV) of 75% and negative predictive value (NPV) of 97%. A combination of the molecular and histological diagnosis had a sensitivity of 91%, specificity of 97%, PPV of 79% and NPV of 99% and the cases that could be diagnosed on uterine aspirate rose from 76 to 93% when combined with the molecular test. Incorporation of the molecular diagnosis increases the reliability of a negative diagnosis, reduces the need for hysteroscopies and helps to identify additional cases., (Copyright © 2013 UICC.)

Endometrial cancer (EC) is the most frequent of the invasive tumors of the female genital tract. Although usually detected in its initial stages, a 20% of the patients present with advanced disease. To date, no characterized molecular marker has been validated for the diagnosis of EC. In addition, new methods for prognosis and classification of EC are needed to combat this deadly disease. We thus aimed to identify new molecular markers of EC and to evaluate their validity on endometrial aspirates. Gene expression screening on 52 carcinoma samples and series of real-time quantitative PCR validation on 19 paired carcinomas and normal tissue samples and on 50 carcinoma and noncarcinoma uterine aspirates were performed to identify and validate potential biomarkers of EC. Candidate markers were further confirmed at the protein level by immunohistochemistry and Western blot. We identified ACAA1, AP1M2, CGN, DDR1, EPS8L2, FASTKD1, GMIP, IKBKE, P2RX4, P4HB, PHKG2, PPFIBP2, PPP1R16A, RASSF7, RNF183, SIRT6, TJP3, EFEMP2, SOCS2 and DCN as differentially expressed in ECs. Furthermore, the differential expression of these biomarkers in primary endometrial tumors is correlated to their expression level in corresponding uterine fluid samples. Finally, these biomarkers significantly identified EC with area under the receiver-operating-characteristic values ranging from 0.74 to 0.95 in uterine aspirates. Interestingly, analogous values were found among initial stages. We present the discovery of molecular biomarkers of EC and describe their utility in uterine aspirates. These findings represent the basis for the development of a highly sensitive and specific minimally invasive method for screening ECs., (Copyright © 2011 UICC.)

Endometrial carcinoma is the most common malignancy of the female genital tract in industrialized countries. Metastasis is the major cause of endometrial cancer deaths. Therefore, there is a vital need for clinically relevant in vivo models allowing the elucidation of the molecular and cellular mechanisms underlying metastatic behavior. In this study, we describe an innovative experimental orthotopic model of human endometrial carcinoma. Implantation in the bifurcation of the uterine horns resulted in tumors integrated into the myometrial compartment, which can be used and further exploited for the study of in vivo angiogenesis, myometrial invasion, and the metastatic capacity of endometrial cancer cells. This orthotopic model also represents a suitable tool to analyze how tumorigenesis and distant metastasis of endometrial cancer might be influenced by gene alteration, by modulating its expression in the original cancer cell line. One of the candidate genes implicated in endometrial cancer is the transcription factor RUNX1. The over-expression of RUNX1 in the endometrial cancer cell line HEC1A and the transplantation of these cells to the uterus of nude mice were associated specifically with distant metastasis in the lung. RUNX1 plays a role in the establishment of metastases in endometrial cancer. Translated to the clinics, these models would be equivalent to an advanced undifferentiated carcinoma with node affectation (stage IIIC) and distant metastasis (stage IVB). These patients would be candidates for adjuvant therapy, not efficient until today, and therefore, our models are actually suitable for the design and evaluation of experimental therapies., (Copyright 2009 UICC.)