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The tumor suppressor miR-34 family is transcriptionally induced by p53. Clinical significance of the various miR-34 family members has not been studied in ovarian cancer. In 228 ovarian cancers and in 19 non-neoplastic fallopian tube samples we analysed miR-34 a/b/c expression in relation to clinicopathological characteristics and clinical outcome. We found significantly lower levels of miR-34 a/b/c in ovarian cancers as compared to control-tissues (P=0.002, P

Background Mutations in BRCA1 and BRCA2 are associated with better survival in ovarian cancer (OC) patients due to a better response to platinum-based chemotherapy. However, the impact of the BRCA1/2 mRNA-expression is not well characterized in OC. Patients and methods We investigated BRCA1/2 mRNA-expression in 12 non-neoplastic fallopian tubes and 201 epithelial OCs in relation to their clinical characteristics. Results We found higher BRCA1/2 mRNA-expression in OCs compared to controls (P = 0.011, P

Introduction/Background Mutations in cancer susceptibility genes BRCA1/2 are considered to be associated with better survival in ovarian cancer (OC) patients possibly due to a better response to platinum based chemotherapy and PARP inhibitors. However, the impact of the BRCA1/2 mRNA-expression is not well characterized in OC, but could also influence the platinum response and thus predict the clinical outcome in OC patients. Our previous studies have shown that low BRCA1-expression was associated with favorable overall survival (OS) and low BRCA2-expression with better progression-free survival (PFS) and OS in 201 OC patients. The aim of the present study was to validate the prognostic impact of BRCA expression in OC using the TCGA (The Cancer Genome Atlas) cohort. Methodology Clinical and genomic data were obtained from the OC Dataset of The Cancer Genome Atlas (n=581). Overall and progression free survival was estimated using Kaplan-Meier plots and Cox-Regression. Optimal cut off points were defined using Youden index. Results Univariate survival analysis showed that low BRCA2 expression was associated with favorable PFS (p=0.029) and OS (p=0.011). Multivariable survival analysis confirmed the prognostic value of BRCA2 expression both for PFS and OS. Conclusion Low expression of BRCA2 predicts better survival in patients with OC. Our findings may reflect higher platinum-sensitivity due to reduced capacity of DNA damage repair in tissues with low BRCA2 expression. In this context, especially in BRCA-wildtype cancers BRCA2 expression could also be potential predictor for PARP sensitivity. Disclosure Nothing to disclose.

Introduction/Background The SWI/SNF complex - a chromatin remodelling complex - is recurrently mutated and inactivated in ∼20% of human cancers. Mutations of the SMARCA4 gene, which encodes the ATPase of the SWI/SNF complex, can be found in the majority of small cell carcinomas of the ovary, hypercalcaemic type (SCCOHT). EZH2 is the catalytic subunit of the PCR2 complex, which is an opponent of the SWI/SNF complex. EZH2 inhibitors could play a potential role in the therapy of SCCOHT. The aim of this study was to explore the role of SMARCA4 mRNA-expression in ovarian cancer. Methodology SMARCA4 mRNA-expression was investigated in 20 non-neoplastic fallopian tubes and 276 ovarian carcinomas (OC) (including 144 high grade serous ovarian carcinomas, HGSOC) in relation to their clinical characteristics, p53- and BRCA1/2- mutational status, BRCA1/2 mRNA-expression and EZH2 mRNA-expression. Results The SMARCA4 mRNA-expression in OCs was significantly higher compared to the control group (P A subgroup-analysis of HGSOC showed higher SMARCA4-expression in patients younger than 65 years (P=0,021), in patients without residual disease after surgical debulking (P=0,008) and in patients with early FIGO stages I-II (P=0,004). High SMARCA4-expression was associated with better progression-free survival (PFS) (P=0,05) and better overall survival (OS) (P=0,002). Patients with p53-mutations showed higher SMARCA4-expression (P=0,004). There was a significant correlation between the expression of SMARCA4 and EZH2 (P=0,000 r=0,377). Multivariate Cox-regression model revealed independency of the prognostic value of SMARCA4-expression for OS in patients under the age of 65 years (P=0,015). Conclusion High SMARCA4-expression in patients with HGSOC is associated with younger age at onset of disease, early FIGO stage and with absence of residual disease after primary debulking. In patients younger than 65 years, high SMARCA4-expression is independently associated with better overall survival. Disclosure Nothing to disclose.

Introduction/Background The tumor suppressor miR-34 family is transcriptionally induced by p53. Clinical significance of the various miR-34 family members has not been studied in ovarian cancer. Methodology In 228 ovarian cancers and in 19 non-neoplastic fallopian tube samples we analysed miR-34a/b/c expression in relation to clinicopathological characteristics and clinical outcome. Results We found significantly lower levels of miR-34a/b/c in ovarian cancers as compared to control-tissues (P=0.002, P Conclusion Our findings suggest that downregulation of miR-34 family is a crucial part in ovarian cancer development. Low miR-34 levels are linked to a worse overall survival and progression free survival and may indicate a more aggressive disease. Disclosure Nothing to disclose.

Inflammation plays a crucial role in the pathogenesis of cancer with tumor necrosis factor-α (TNF-α) as a key mediator. Recently, spermatogenesis-associated protein 2 (SPATA2) was identified as a TNF receptor modulator which is required for TNF-induced inflammation and apoptosis. The available data on TNF-α in ovarian cancer (OC) are inconsistent, and SPATA2 is completely uncharacterized in tumorigenesis. We analyzed expression of SPATA2 and TNFA by quantitative real-time polymerase chain reaction in tissues of 171 patients with low-grade serous (LGSOC), high-grade serous (HGSOC), endometrioid and clear cell OC compared with 28 non-malignant control tissues. We stimulated OC cells (OVCAR3) with pro-inflammatory (TNF-α, interleukin [IL]-1β) and mitogenic stimuli (IL-6, lysophosphatidic acid) to establish a direct effect between inflammatory signaling and SPATA2. Pro-inflammatory, but not mitogenic stimuli, potently induced SPATA2 expression in OC cells. Expression of TNFA and SPATA2 was higher in OC compared with control tissues (P = 0.010 and P = 0.001, respectively) and correlated with each other (P = 0.034, rs = 0.198). When compared with grade 1 cancers, SPATA2 was expressed higher in grade 2 and 3 tumors (P = 0.011) as well as in HGSOC compared with LGSOC (P = 0.024). Multivariate survival analyses revealed that OC with high SPATA2 expression were associated with reduced progression-free survival (P = 0.048) and overall survival (P < 0.001). In conclusion, SPATA2 expression is regulated by TNF-α and IL-1β and is found to independently affect clinical outcome in OC patients. These data implicate a role of SPATA2 in tumorigenesis which warrants further investigation in gynecological malignancies.

The aim of this study was to explore the role of NOX4 in the biology of the normal endometrium and endometrial cancer. NOX4 plays a key role in other adenocarcinomas and has been implicated in the pathogenesis of diabetes and obesity, which are important risk factors for endometrial cancer. NOX4 expression was assessed in 239 endometrial cancer and 25 normal endometrium samples by quantitative real-time polymerase chain reaction, in situ hybridization, and immunohistochemistry. DNA methylation of the NOX4 promoter was determined by means of MethyLight PCR. Data were correlated with clinicopathological parameters and analyzed in the context of diabetes and body mass index. In the normal endometrium, NOX4 microRNA expression was significantly higher in the secretory transformed compared with proliferative endometrium ( p = 0.008). In endometrial cancer specimens, NOX4 expression did not differ between diabetic and non-diabetic patients, but was the highest in patients with a body mass index ≤ 26 ( p = 0.037). The lowest NOX4 expression was found in carcinosarcomas ( p = 0.007). High NOX4 expression predicted poorer clinical outcome with regard to overall survival, especially in non-diabetic patients and those with a body mass index > 20. Independent prognostic significance of NOX4 transcripts was retained in type I endometrial cancer and was the most meaningful in patients with a body mass index > 20. No prognostic impact was shown for NOX4 promoter methylation in endometrial cancer. For the first time, we demonstrate that NOX4 plays a considerable role in the cycle-dependent changes in the normal endometrium and in the biology of endometrial cancer.