Survival In Serous Ovarian Cancer Patients Research Articles

Chromosome instability region analysis and identification of the driver genes of the epithelial ovarian cancer cell lines A2780 and SKOV3.

Epithelial ovarian cancer (EOC) is one of the most prevalent gynaecological cancers worldwide. The molecular mechanisms of serous ovarian cancer (SOC) remain unclear and not well understood. SOC cases are primarily diagnosed at the late stage, resulting in a poor prognosis. Advances in molecular biology techniques allow us to obtain a better understanding of precise molecular mechanisms and to identify the chromosome instability region and key driver genes in the carcinogenesis and progression of SOC. Whole-exome sequencing was performed on the normal ovarian cell line IOSE80 and the EOC cell lines SKOV3 and A2780. The single-nucleotide variation burden, distribution, frequency and signature followed the known ovarian mutation profiles, without chromosomal bias. Recurrently mutated ovarian cancer driver genes, including LRP1B, KMT2A, ARID1A, KMT2C and ATRX were also found in two cell lines. The genome distribution of copy number alterations was found by copy number variation (CNV) analysis, including amplification of 17q12 and 4p16.1 and deletion of 10q23.33. The CNVs of MED1, GRB7 and MIEN1 located at 17q12 were found to be correlated with the overall survival of SOC patients (MED1: p = 0.028, GRB7: p = 0.0048, MIEN1: p = 0.0051), and the expression of the three driver genes in the ovarian cell line IOSE80 and EOC cell lines SKOV3 and A2780 was confirmed by western blot and cell immunohistochemistry.

Association of oncostatin M receptor polymorphisms with clinical recurrence of ovarian cancer in theChinese Han population.

Aim: Ovarian cancer (OC) is a gynecological malignancy with a challenging judgment of prognosis due tocomplicated etiology and high recurrence rate. The oncostatin M receptor (OSMR) from members of theIL-6 receptor family is associated with tumor development. This study aims to explore the correlations between OSMR gene polymorphisms (rs2278329 [G/A, missense, Asp553Asn], rs2292016 [G/T, promoter, -100G/T]) and OC. Methods: This study enrolled 160 OC patients and 397 healthy controls. Genotypes of two single-nucleotide polymorphismswere distinguished using TaqMan SNP Genotyping Assay, and statistical analysis was performed using SPSS software. Results: A significantly decreased overall survival rate was found in serous OC patients carrying rs2278329 GA/AA genotypes. Meanwhile, TT genotype carriers of rs2292016 had an improved relapse rate, and theGT genotype showed a definitive correlation with a lower relapse rate. Conclusion:OSMR gene polymorphisms may be related to recurrence and overall survival of serous OC patients.

Abstract 626: The neoantigen and immune landscape of epithelial mesenchymal transition (EMT) low and high score serous ovarian cancers

Abstract Background: Apart from its role in ovarian cancer progression, epithelial-mesenchymal transition (EMT) can promote chemotherapy resistance. We aimed to analyze how the EMT score would affect the tumor microenvironment in ovarian cancer. Methods: cBioportal was queried to obtain The Cancer Genome Atlas (TCGA) data for the serous ovarian cancer (SOC) cohort (TCGA, 585 patients). The neoantigen prediction data was derived from the CloudNeo pipeline using TCGA mutation calling. EMT scores were calculated by subtracting the average RNA-seq z-scores of three epithelial marker genes from the average RNA-seq z-scores of 13 mesenchymal marker genes as described in the previous study. Patient samples were grouped as either EMT-high (highest 1/3) or EMT-low (lowest 1/3). CIBERSORT was applied to predict the tumor-infiltrating immune cells. Results: Among the 585 SOC patients, only 256 patients had mutation data available for our analysis. The EMT-low group had a significantly higher mutation count (p value=0.0004) and cytolytic score (p value=0.032) than the EMT-high group. In addition, the EMT-low samples were associated with improved overall survival in SOC patients (HR, 0.55; 95% CI, 0.39-0.78; P < 0.001). The median survival of EMT-low was 57.40, and EMT-high was 41.06 months. Neoantigen counts and PD-L1 express level tended to be higher in the EMT-high group although failed to show statistical significance. The immune cell infiltration rates were not different between both groups. Conclusions: Our study is the first to describe the association between the EMT potential, neoantigen counts, and cytolytic scores in SOC. In our analyses, tumors with low EMT potential had a significantly higher neoantigen burden and higher cytolytic scores, suggesting that tumors with low EMT potentials tend to be more immunogenic. Further studies are warranted to explore the utility of EMT scores as biomarkers to predict the treatment response to immunotherapy in SOC. The immunologic characteristics of EMT low and high SOCNumber of patientsNeoantigen countp-valueMutation countp-valueCytolytic scorep-valuePD-L1 expressionp-valueEMT low6088.190.183783.190.0004183.40.032190.0663EMT high5867.7472.7486.3515.52 Citation Format: Won Kyung Hur, Jin Young Hwang, Leeseul Kim, Myungwoo Nam, William H. Bae, Yoonhee Choi, Yeun Ho Lee, Heayoon S. Cho, Emma Yu, Chan Mi Jung, William Cheng, Eugene Kim, Christmann Low, Victor Wang, Jeff Chuang, Young Kwang Chae. The neoantigen and immune landscape of epithelial mesenchymal transition (EMT) low and high score serous ovarian cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 626.

Development of a novel transcription factors-related prognostic signature for serous ovarian cancer

Growing evidence suggest that transcription factors (TFs) play vital roles in serous ovarian cancer (SOC). In the present study, TFs mRNA expression profiles of 564 SOC subjects in the TCGA database, and 70 SOC subjects in the GEO database were screened. A 17-TFs related prognostic signature was constructed using lasso cox regression and validated in the TCGA and GEO cohorts. Consensus clustering analysis was applied to establish a cluster model. The 17-TFs related prognostic signature, risk score and cluster models were effective at accurately distinguishing the overall survival of SOC. Analysis of genomic alterations were used to elaborate on the association between the 17-TFs related prognostic signature and genomic aberrations. The GSEA assay results suggested that there was a significant difference in the inflammatory and immune response pathways between the high-risk and low-risk score groups. The potential immune infiltration, immunotherapy, and chemotherapy responses were analyzed due to the significant difference in the regulation of lymphocyte migration and T cell-mediated cytotoxicity between the two groups. The results indicated that patients with low-risk score were more likely to respond anti-PD-1, etoposide, paclitaxel, and veliparib but not to gemcitabine, doxorubicin, docetaxel, and cisplatin. Also, the prognostic nomogram model revealed that the risk score was a good prognostic indicator for SOC patients. In conclusion, we explored the prognostic values of TFs in SOC and developed a 17-TFs related prognostic signature to predict the survival of SOC patients.

Decreased expression of ALDH5A1 predicts prognosis in patients with ovarian cancer

ABSTRACTAldehyde dehydrogenase 5 family, member A1 (ALDH5A1) belongs to the superfamily of aldehyde dehydrogenases (ALDHs). However, the prognostic value of ALDH5A1 in ovarian cancer remains unclear. The aim of this study was to explore the relationship between ALDH5A1 and the prognosis of patients with ovarian cancer (OC). We compared the expression of ALDH5A1 in OC to that innormal controls, using GSE40595 profiling data. Tissue microarray analysis was conducted for192 OC patients, 14 adjacent normal ovary tissues, and 2 normal ovary tissues. Using the “Kaplan-Meier plotter” (KM plotter) database, updated gene expression data and survival information of a total of 1583 OC patients were used to evaluate the prognostic value of ALDH5A1 in OC patients. We found that ALDH5A1 mRNA expression was downregulated in OC patients compared with that innormal tissues. In survival analyses, we found that ALDH5A1 was positively linked to prognosis in patients with OC, particularly in those with serous ovarian cancer (SOC). In addition, high Ctranscription activity of ALDH5A1 was correlated with better overall survival in SOC patients expressing mutatedTP53, but not in those expressing wild-type TP53. In pathological grades II/III, a high mRNA level of ALDH5A1 was associated with improved overall survival. The positive association between ALDH5A1 and prognosis was found not only in early stages(I and II), but also in advanced stages (III and IV) of SOC patients. results indicate that ALDH5A1 is an excellent predictive factor of OC and may play crucial roles in OC progression.

Long non-coding RNA ANRIL predicts poor prognosis and promotes invasion/metastasis in serous ovarian cancer.

Recent studies have highlighted the role of long non-coding RNAs (lncRNAs) in carcinogenesis and have suggested that genes of this class might be used as biomarkers in cancer. However, whether lncRNAs are involved in serous ovarian cancer (SOC) remains largely unknown. In the present study, we focused on lncRNA antisense non-coding RNA in the INK4 locus (ANRIL) and investigated its expression pattern, clinical significance, and biological function in SOC. We found that ANRIL levels were elevated in SOC tissues compared with normal controls and were highly correlated with advanced FIGO stage, high histological grade, lymph node metastasis, and poor prognosis. Multivariate analysis further revealed that ANRIL is an independent prognostic factor for predicting overall survival of SOC patients. In vitro, we compared differential ANRIL levels between SOC parental cell lines (SK-OV-3, HO8910) and highly metastatic sublines (SK-OV-3.ip1, HO8910-PM). Notably, ANRIL was highly expressed in both SK-OV-3.ip1 cells and HO8910-PM cells. SiRNA-mediated ANRIL silencing in these cells impaired cell migration and invasion. Based on the metastasis-related mRNA microarray analysis and subsequent western blotting confirmation, we found that MET and MMP3 are key downstream genes of ANRIL involved in SOC cell migration/invasion. Together, our data suggest that lncRNA ANRIL plays an important role in SOC invasion/metastasis and could represent a novel biomarker for predicting poor survival as well a promising therapeutic target.

The long non-coding RNA HOTAIR promotes the proliferation of serous ovarian cancer cells through the regulation of cell cycle arrest and apoptosis

HOX transcript antisense RNA (HOTAIR) is a well-known long non-coding RNA (lncRNA) whose dysregulation correlates with poor prognosis and malignant progression in many forms of cancer. Here, we investigate the expression pattern, clinical significance, and biological function of HOTAIR in serous ovarian cancer (SOC). Clinically, we found that HOTAIR levels were overexpressed in SOC tissues compared with normal controls and that HOTAIR overexpression was correlated with an advanced FIGO stage and a high histological grade. Multivariate analysis revealed that HOTAIR is an independent prognostic factor for predicting overall survival in SOC patients. We demonstrated that HOTAIR silencing inhibited A2780 and OVCA429 SOC cell proliferation in vitro and that the anti-proliferative effects of HOTAIR silencing also occurred in vivo. Further investigation into the mechanisms responsible for the growth inhibitory effects by HOTAIR silencing revealed that its knockdown resulted in the induction of cell cycle arrest and apoptosis through certain cell cycle-related and apoptosis-related proteins. Together, these results highlight a critical role of HOTAIR in SOC cell proliferation and contribute to a better understanding of the importance of dysregulated lncRNAs in SOC progression.

Elevated AKAP12 in paclitaxel-resistant serous ovarian cancer cells is prognostic and predictive of poor survival in patients.

A majority of high-grade (HG) serous ovarian cancer (SOC) patients develop resistant disease despite high initial response rates to platinum/paclitaxel-based chemotherapy. We identified shed/secreted proteins in preclinical models of paclitaxel-resistant human HGSOC models and correlated these candidate proteins with patient outcomes using public data from HGSOC patients. Proteomic analyses of a HGSOC cell line secretome was compared to those from a syngeneic paclitaxel-resistant variant and from a line established from an intrinsically chemorefractory HGSOC patient. Associations between the identified candidate proteins and patient outcome were assessed in a discovery cohort of 545 patients and two validation cohorts totaling 795 independent SOC patients. Among the 81 differentially abundant proteins identified (q < 0.05) from paclitaxel-sensitive vs -resistant HGSOC cell secretomes, AKAP12 was verified to be elevated in all models of paclitaxel-resistant HGSOC. Furthermore, elevated AKAP12 transcript expression was associated with worse progression-free and overall survival. Associations with outcome were observed in three independent cohorts and remained significant after adjusted multivariate modeling. We further provide evidence to support that differential gene methylation status is associated with elevated expression of AKAP12 in taxol-resistant ovarian cancer cells and ovarian cancer patient subsets. Elevated expression and shedding/secretion of AKAP12 is characteristic of paclitaxel-resistant HGSOC cells, and elevated AKAP12 transcript expression is a poor prognostic and predictive marker for progression-free and overall survival in SOC patients.