Integrated microRNA and mRNA signatures associated with overall survival in epithelial ovarian cancer

Ovarian cancer (OC), the eighth-leading cause of cancer-related death among females worldwide, is mainly represented by epithelial OC (EOC) that can be further subdivided into four subtypes: serous (75%), endometrioid (10%), clear cell (10%), and mucinous (3%). Major reasons for high mortality are the poor biological understanding of the OC mechanisms and a lack of reliable markers defining each EOC subtype. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression primarily by targeting messenger RNA (mRNA) transcripts. Their aberrant expression patterns have been associated with cancer development, including OC. However, the role of miRNAs in tumorigenesis is still to be determined, mainly due to the lack of consensus regarding optimal methodologies for identification and validation of miRNAs and their targets. Several tools for computational target prediction exist, but false interpretations remain a problem. The experimental validation of every potential miRNA-mRNA pair is not feasible, as it is laborious and expensive. In this study, we analyzed the correlation between global miRNA and mRNA expression patterns derived from microarray profiling of 197 EOC patients to identify the signatures of miRNA-mRNA interactions associated with overall survival (OS). The aim was to investigate whether these miRNA-mRNA signatures might have a prognostic value for OS in different subtypes of EOC. The content of our cohort (162 serous carcinomas, 15 endometrioid carcinomas, 11 mucinous carcinomas, and 9 clear cell carcinomas) reflects a real-world scenario of EOC. Several interaction pairs between 6 miRNAs (hsa-miR-126-3p, hsa-miR-223-3p, hsa-miR-23a-5p, hsa-miR-27a-5p, hsa-miR-486-5p, and hsa-miR-506-3p) and 8 mRNAs (ATF3, CH25H, EMP1, HBB, HBEGF, NAMPT, POSTN, and PROCR) were identified and the findings appear to be well supported by the literature. This indicates that our study has a potential to reveal miRNA-mRNA signatures relevant for EOC. Thus, the evaluation on independent cohorts will further evaluate the performance of such findings.

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Salvage radiation therapy for localized recurrent ovarian cancer

International Journal of Gynecological Cancer ◽

10.1136/ijgc-2019-000247 ◽

2019 ◽

Vol 29 (5) ◽

pp. 916-921

Author(s):

Alicia Smart ◽

Yu-Hui Chen ◽

Teresa Cheng ◽

Martin King ◽

Larissa Lee

Keyword(s):

Ovarian Cancer ◽

Overall Survival ◽

Clear Cell ◽

Recurrent Ovarian Cancer ◽

Salvage Radiotherapy ◽

Platinum Sensitive ◽

Long Term Survivors ◽

Disease Free

IntroductionTo evaluate clinical outcomes for patients with localized recurrent ovarian cancer treated with salvage radiotherapy.MethodsIn a retrospective single institutional analysis, we identified 40 patients who received salvage radiotherapy for localized ovarian cancer recurrence from January 1995 to June 2011. Recurrent disease was categorized as: pelvic peritoneal (45%, 18), extraperitoneal/nodal (35%, 14), or vaginal (20%, eight). Actuarial disease-free and overall survival estimates were calculated by Kaplan–Meier and prognostic factors evaluated by the Cox proportional hazards model.ResultsMedian follow-up was 42 months. Median patient age was 54 years (range, 27–78). Histologic subtypes were: serous (58%, 23), endometrioid (15%, six), clear cell (13%, five), mucinous (8%, three), and other (8%, three). At the time of salvage radiotherapy, surgical cytoreduction was performed in 60% (24) and 68% (27) had platinum-sensitive disease. Most patients (63%, 25) received salvage radiotherapy at the time of first recurrence. Relapse after salvage radiotherapy occurred in 29 patients at a median time of 16 months and was outside the radiotherapy field in 62%. 18 At 3 years, disease-free and overall survival rates were 18% and 80%, respectively. On multivariate analysis, non-serous histology (hazards ratio 0.3, 95% CI 0.1–0.7) and platinum-sensitivity (hazards ratio 0.2, 95% CI 0.1–0.5) were associated with lower relapse risk. Platinum-sensitivity was also associated with overall survival (hazards ratio 0.4, 95% CI 0.1–1.0). Four patients (10%) were long-term survivors without recurrence 5 years after salvage radiotherapy. Of the five patients with clear cell histology, none experienced relapse at the time of last follow-up.DiscussionPatients with non-serous and/or platinum-sensitive ovarian cancer had the greatest benefit from salvage radiotherapy for localized recurrent disease. Although relapse was common, radiotherapy prolonged recurrence for > 1 year in most patients and four were long-term survivors.

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Does endometriosis have an effect on the survival of women with synchronous endometrial and ovarian cancer?

Journal of Endometriosis and Pelvic Pain Disorders ◽

10.1177/2284026519893537 ◽

2019 ◽

Vol 11 (4) ◽

pp. 185-193

Author(s):

Engin Celik ◽

Hale Goksever Celik ◽

Hamdullah Sozen ◽

Semen Onder ◽

Merve Baktiroglu ◽

...

Keyword(s):

Ovarian Cancer ◽

Overall Survival ◽

Confidence Interval ◽

Detrimental Effect ◽

Clear Cell ◽

Cell Cancer ◽

Progression Free Survival ◽

Hazard Ratio ◽

Free Survival ◽

Pathological Characteristics

Purpose: Synchronous endometrial and ovarian cancer is defined as the concurrent presence of ovarian cancer with endometrial cancer. We aimed to evaluate whether there is an effect of endometriosis on progression-free survival and overall survival of women with synchronous endometrial and ovarian cancer. We also compared these findings with the patients having endometrial-only tumors and ovarian-only tumors. Methods: The patients who underwent surgery for endometrioid or clear-cell endometrial-only tumors and/or ovarian-only tumors and synchronous endometrial and ovarian cancer between 2005 and 2016 were included in this cohort study. The effect of the presence of endometriosis on progression-free survival and overall survival in these women who met the criteria was determined using statistical methods. Women were also compared regarding their demographic, clinical, and pathological characteristics. Results: A total of 176 patients were included in this study. All histology types of tumors located in endometrium or ovary were endometrioid or clear-cell cancer. Endometriosis was present in 62 patients (35.2%), whereas adenomyosis was present in 44 patients (25%). Endometriosis was diagnosed more frequently in women with ovarian-only tumors and synchronous endometrial and ovarian cancer than those with endometrial-only tumors (59.2% vs 5.7%, p < 0.001 and 45.7% vs 5.7%, p < 0.001, respectively). The patients with endometriosis showed no significantly longer progression-free survival and overall survival (hazard ratio = 1.70; 95% confidence interval = 0.48–6.03; p = 0.408 and hazard ratio = 1.67; 95% confidence interval = 0.30–9.44; p = 0.562, respectively). The presence of endometriosis was a stronger predictor for progression-free survival and overall survival comparing with the presence of adenomyosis. Conclusion: The women with synchronous endometrial and ovarian cancer should be informed that endometriosis has no detrimental effect on progression-free survival and overall survival.

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Emerging Roles of Estrogen-Regulated Enhancer and Long Non-Coding RNAs

International Journal of Molecular Sciences ◽

10.3390/ijms21103711 ◽

2020 ◽

Vol 21 (10) ◽

pp. 3711

Author(s):

Melina J. Sedano ◽

Alana L. Harrison ◽

Mina Zilaie ◽

Chandrima Das ◽

Ramesh Choudhari ◽

...

Keyword(s):

Rna Sequencing ◽

Expression Patterns ◽

Biological Significance ◽

Rna Seq ◽

Biological Functions ◽

Protein Coding ◽

Rna Molecules ◽

Non Coding Rna ◽

Genome Wide ◽

Non Coding Rnas

Genome-wide RNA sequencing has shown that only a small fraction of the human genome is transcribed into protein-coding mRNAs. While once thought to be “junk” DNA, recent findings indicate that the rest of the genome encodes many types of non-coding RNA molecules with a myriad of functions still being determined. Among the non-coding RNAs, long non-coding RNAs (lncRNA) and enhancer RNAs (eRNA) are found to be most copious. While their exact biological functions and mechanisms of action are currently unknown, technologies such as next-generation RNA sequencing (RNA-seq) and global nuclear run-on sequencing (GRO-seq) have begun deciphering their expression patterns and biological significance. In addition to their identification, it has been shown that the expression of long non-coding RNAs and enhancer RNAs can vary due to spatial, temporal, developmental, or hormonal variations. In this review, we explore newly reported information on estrogen-regulated eRNAs and lncRNAs and their associated biological functions to help outline their markedly prominent roles in estrogen-dependent signaling.

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Long non-coding RNAs in brain tumors: roles and potential as therapeutic targets

Journal of Hematology & Oncology ◽

10.1186/s13045-021-01088-0 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Sung-Hyun Kim ◽

Key-Hwan Lim ◽

Sumin Yang ◽

Jae-Yeol Joo

Keyword(s):

Brain Tumors ◽

Molecular Mechanisms ◽

Expression Patterns ◽

Tumor Therapy ◽

Adverse Outcomes ◽

Biological Functions ◽

Aberrant Expression ◽

Biological Phenomena ◽

Non Coding Rna ◽

Non Coding Rnas

AbstractBrain tumors are associated with adverse outcomes despite improvements in radiation therapy, chemotherapy, and photodynamic therapy. However, treatment approaches are evolving, and new biological phenomena are being explored to identify the appropriate treatment of brain tumors. Long non-coding RNAs (lncRNAs), a type of non-coding RNA longer than 200 nucleotides, regulate gene expression at the transcriptional, post-transcriptional, and epigenetic levels and are involved in a variety of biological functions. Recent studies on lncRNAs have revealed their aberrant expression in various cancers, with distinct expression patterns associated with their instrumental roles in cancer. Abnormal expression of lncRNAs has also been identified in brain tumors. Here, we review the potential roles of lncRNAs and their biological functions in the context of brain tumors. We also summarize the current understanding of the molecular mechanisms and signaling pathways related to lncRNAs that may guide clinical trials for brain tumor therapy.

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Squalene Epoxidase Correlates E-Cadherin Expression and Overall Survival in Colorectal Cancer Patients: The Impact on Prognosis and Correlation to Clinicopathologic Features

Journal of Clinical Medicine ◽

10.3390/jcm8050632 ◽

2019 ◽

Vol 8 (5) ◽

pp. 632 ◽

Cited By ~ 2

Author(s):

Joo Heon Kim ◽

Chang Nam Kim ◽

Dong Wook Kang

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Regional Lymph Node ◽

Expression Patterns ◽

Squalene Epoxidase ◽

Poor Overall Survival ◽

Aberrant Expression ◽

Mesenchymal Transition ◽

The Impact ◽

E Cadherin

Squalene epoxidase (SE), coded by SQLE, is an important rate-limiting enzyme in the cholesterol biosynthetic pathway. Recently, the aberrant expression of SQLE, which is responsible for epithelial to mesenchymal transition (EMT), has been reported in various types of cancer. This study was undertaken to clarify the clinicopathologic implications of SE in patients with stage I to IV colorectal cancer (CRC). We also analyzed the expression patterns of SE in association with E-cadherin in a series of CRCs. We detected the cytoplasmic expression of SE in 59.4% of carcinoma samples by immunohistochemistry (IHC). There was a significant correlation between a high level of SE expression and lymphovascular (LV) invasion (p < 0.001), tumor budding (p < 0.001), invasion depth (p = 0.002), regional lymph node metastasis (p < 0.001), and pathologic TNM stage (p < 0.001). SE is more abundantly expressed at the invasive front, and reversely correlated with E-cadherin expression. Patients with SE-positive CRC had shorter recurrence-free survival (RFS) and poor overall survival (OS) than those with SE-negative CRC in multivariate analysis (p < 0.001 and p < 0.001, respectively). These data suggest that SE can serve as a valuable biomarker for unfavorable prognosis, and as a possible therapeutic target in CRCs.

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Result of interim analysis of overall survival in the GCIG ICON7 phase III randomized trial of bevacizumab in women with newly diagnosed ovarian cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.18_suppl.lba5006 ◽

2011 ◽

Vol 29 (18_suppl) ◽

pp. LBA5006-LBA5006 ◽

Cited By ~ 28

Author(s):

G. Kristensen ◽

T. Perren ◽

W. Qian ◽

J. Pfisterer ◽

J. A. Ledermann ◽

...

Keyword(s):

Ovarian Cancer ◽

Overall Survival ◽

High Risk ◽

Subgroup Analysis ◽

Interim Analysis ◽

Poor Prognosis ◽

Clear Cell ◽

Phase Iii ◽

Newly Diagnosed ◽

Early Stage Disease

LBA5006 Background: ICON7 was designed to investigate safety and efficacy of adding bevacizumab to standard chemotherapy in women with newly diagnosed ovarian cancer. Analyses of mature progression-free survival (PFS) data suggest a PFS benefit from bevacizumab (p=0.0041, a 15% improvement at 12 months and 1.5 months overall), and a trend for overall survival (OS) improvement, hazard ratio (HR)=0.81, 95%CI=0.63 to 1.04, p =0.098. The final analysis of OS will be performed when 715 deaths have occurred. An interim analysis with at least 365 deaths was requested by regulatory authorities considering licensing. This was approved by the independent data monitoring and steering committees. A subgroup analysis for poor prognosis patients (FIGO III debulked to >1.0cm or FIGO IV with debulking) was performed in an exploratory manner. Methods: Eligible women with high-risk early (FIGO stage I or IIa (grade 3 or clear cell), capped ≤10%) or advanced (stage IIb-IV) epithelial ovarian, primary peritoneal or fallopian tube cancer were randomised (1:1) to 6 cycles of 3 weekly chemotherapy (carboplatin AUC 5 or 6 and paclitaxel 175mg/m2) alone, or the same chemotherapy given concurrently with bevacizumab (7.5mg/kg) for 5 or 6 cycles followed by continued 3-weekly single-agent bevacizumab for 12 additional cycles or until progression whichever was the earlier. Results: From December 2006 to February 2009, 1,528 women were randomised from 263 centres in 7 GCIG groups. Baseline characteristics were balanced between arms: median age (57 years); ECOG PS 0-1 (47%); high-risk early-stage disease (9%); poor prognosis patients (30%); histology (69% serous, 8% endometrioid, 8% clear cell). Overall OS analysis: median follow-up 28 months, 377 deaths (200 standard, 177 bevacizumab), HR=0.84, 95%CI=0.69 to 1.03, p=0.099. Exploratory subgroup analysis of poor prognosis patients: 188 deaths (109 standard, 79 bevacizumab), HR=0.64, 95%CI=0.48 to 0.85, p=0.0022 with p=0.015 for test for interaction (treatment/risk group). Conclusions: The overall trend for improvement in OS from bevacizumab continues with a numerically larger benefit in poor prognosis patients.

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NUCKS nuclear elevated expression indicates progression and prognosis of ovarian cancer

Tumor Biology ◽

10.1177/1010428317714631 ◽

2017 ◽

Vol 39 (9) ◽

pp. 101042831771463 ◽

Cited By ~ 3

Author(s):

Ce Shi ◽

Ling Qin ◽

Hongyu Gao ◽

Lina Gu ◽

Chang Yang ◽

...

Keyword(s):

Ovarian Cancer ◽

Overall Survival ◽

Messenger Rna ◽

Disease Free Survival ◽

Rna Expression ◽

Free Survival ◽

Ovarian Cancers ◽

Response To Chemotherapy ◽

Elevated Expression ◽

Disease Free

NUCKS (nuclear, casein kinase, and cyclin-dependent kinase substrate) is implicated in the tumorigenesis of several human malignancies, but its role in ovarian cancer remains unknown. We aim to investigate NUCKS expression and its clinical significance in ovarian cancer. The messenger RNA expression of NUCKS was determined in normal and malignant ovarian tissues using quantitative polymerase chain reaction assay. Immunohistochemistry was applied to detect the status of NUCKS protein expression in 121 ovarian cancer tissues. NUCKS protein high expression was detected in 52 (43.0%) of 121 patients. NUCKS messenger RNA expression was gradually upregulated in non-metastatic ovarian cancers ( n = 20), metastatic ovarian cancers ( n = 20), and its matched metastatic lesions ( n = 20) in comparison with that in normal ovarian tissues ( n = 10; p < 0.05). Elevated expression of NUCKS in ovarian cancer was associated significantly with the Federation of Gynecology and Obstetrics stage ( p = 0.037), histological grade ( p = 0.003), residual disease ( p = 0.013), lymph node metastasis ( p = 0.002), response to chemotherapy ( p < 0.001), and recurrence ( p = 0.013). In the multivariate Cox analysis, NUCKS expression was an independent prognostic marker for overall survival and disease-free survival in ovarian cancer with p values of <0.001 for both. Especially, NUCKS overexpression had prognostic potential for overall survival and disease-free survival ( p < 0.001 for both) in advanced ovarian cancers and only for disease-free survival in early ovarian cancers ( p = 0.017). Our data suggest that NUCKS overexpression may contribute to progression and poor prognosis in ovarian cancer especially in advanced ovarian cancer.

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microRNA and the pathogenesis of ovarian cancer – a new horizon for molecular diagnostics and treatment?

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2011-0847 ◽

2012 ◽

Vol 50 (4) ◽

Cited By ~ 19

Author(s):

Jan Dominik Kuhlmann ◽

Jens Rasch ◽

Pauline Wimberger ◽

Sabine Kasimir-Bauer

Keyword(s):

Ovarian Cancer ◽

Messenger Rna ◽

Target Genes ◽

Mrna Translation ◽

Ovarian Carcinomas ◽

Rna Molecules ◽

Sequence Complementarity ◽

Functional Understanding ◽

Novel Biomarkers ◽

Gene Regulatory

AbstractOvarian cancer is the leading cause of death among gynecologic malignancies and despite advances in treatment, more than 50% of all patients will experience recurrence, resulting in worse overall prognosis. Therefore, identification of novel biomarkers for ovarian cancer is of significant interest. microRNA (miRNA) constitute a class of small gene regulatory RNA molecules (18–24 nt) and by sequence complementarity, they negatively regulate messenger RNA (mRNA) translation of target genes. Rising data are available that miRNA are functionally involved in the pathogenesis of ovarian cancer. In this regard, recent advances in profiling studies revealed a variety of miRNA candidates, differently expressed in ovarian carcinomas and in disease-specific conditions like hypoxia or chemo-resistance. This review abstracts recent efforts on establishing miRNA as novel molecular biomarkers for ovarian cancer and depicts the existing preliminary framework for defining peripheral-blood derived miRNA as novel circulating biomarkers. Beside these clinical implications, we highlight the current functional understanding of miRNA alteration and discuss major challenges in miRNA profiling approaches. Finally, we briefly outline methodologies to therapeutically modulate miRNA expression in cancer and try to assess how miRNA can improve our conceptual understanding and the clinical management of ovarian cancer.

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Integrative analysis of mRNA and miRNA sequencing data for gliomas of various grades

Egyptian Journal of Medical Human Genetics ◽

10.1186/s43042-020-00119-8 ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Dmitry Y. Gvaldin ◽

Anton A. Pushkin ◽

Nataliya N. Timoshkina ◽

Eduard E. Rostorguev ◽

Arbi M. Nalgiev ◽

...

Keyword(s):

Overall Survival ◽

Mirna Expression ◽

Interaction Analysis ◽

Expression Profiles ◽

Expression Patterns ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Differential Analysis ◽

Sequencing Data ◽

Aberrant Expression

Abstract Background The purpose of this study was to characterize subtype-specific patterns of mRNA and miRNA expression of gliomas using The Cancer Genome Atlas (TCGA) data to search for genetic determinants that predict prognosis in terms of overall survival and to create interaction networks for grade 2 and 3 (G2 and G3) astrocytomas, oligodendrogliomas and grade 4 (G4) glioblastoma multiforme. Based on open-access TCGA data, 5 groups were formed: astrocytoma G2 (n = 58), astrocytoma G3 (n = 128), oligodendroglioma G2 (n = 102), oligodendroglioma G3 (n = 72) and glioblastoma G4 (n = 564); normal samples of brain tissue were also analysed (n = 15). Data of patient age, sex, survival and expression patterns of mRNA and miRNA were extracted for each sample. After stratification of the data into groups, a differential analysis of expression was carried out, genes and miRNAs that affect overall survival were identified and gene set enrichment analysis (GSEA) and interaction analysis were performed. Results A total of 939 samples of glial tumours were analysed, for which subtype-specific expression profiles of genes and miRNAs were identified and networks of mRNA-miRNA interactions were constructed. Genes whose aberrant expression level was associated with survival were determined, and pairwise correlations between differential gene expression (DEG) and differential miRNA expression (DE miRNA) were calculated. Conclusions The developed panel of genes and miRNAs allowed us to differentiate glioma subtypes and evaluate prognosis in terms of the overall survival of patients. The regulatory miRNA-mRNA pairs unique to the five glioma subtypes identified in this study can stimulate the development of new therapeutic approaches based on subtype-specific mechanisms of oncogenesis.

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Long-Term Survival Among Histological Subtypes in Advanced Epithelial Ovarian Cancer: Population-Based Study Using the Surveillance, Epidemiology, and End Results Database (Preprint)

10.2196/preprints.25976 ◽

2020 ◽

Author(s):

Shi-Ping Yang ◽

Hui-Luan Su ◽

Xiu-Bei Chen ◽

Li Hua ◽

Jian-Xian Chen ◽

...

Keyword(s):

Ovarian Cancer ◽

Overall Survival ◽

Epithelial Ovarian Cancer ◽

Clear Cell ◽

Histological Subtypes ◽

Cancer Specific Survival ◽

Term Survival ◽

Primary Ovarian Cancer ◽

Advanced Epithelial Ovarian Cancer

BACKGROUND Actual long-term survival rates for advanced epithelial ovarian cancer (EOC) are rarely reported. OBJECTIVE This study aimed to assess the role of histological subtypes in predicting the prognosis among long-term survivors (≥5 years) of advanced EOC. METHODS We performed a retrospective analysis of data among patients with stage III-IV EOC diagnosed from 2000 to 2014 using the Surveillance, Epidemiology, and End Results cancer data of the United States. We used the chi-square test, Kaplan–Meier analysis, and multivariate Cox proportional hazards model for the analyses. RESULTS We included 8050 patients in this study, including 6929 (86.1%), 743 (9.2%), 237 (2.9%), and 141 (1.8%) patients with serous, endometrioid, clear cell, and mucinous tumors, respectively. With a median follow-up of 91 months, the most common cause of death was primary ovarian cancer (80.3%), followed by other cancers (8.1%), other causes of death (7.3%), cardiac-related death (3.2%), and nonmalignant pulmonary disease (3.2%). Patients with the serous subtype were more likely to die from primary ovarian cancer, and patients with the mucinous subtype were more likely to die from other cancers and cardiac-related disease. Multivariate Cox analysis showed that patients with endometrioid (hazard ratio [HR] 0.534, P<.001), mucinous (HR 0.454, P<.001), and clear cell (HR 0.563, P<.001) subtypes showed better ovarian cancer-specific survival than those with the serous subtype. Similar results were found regarding overall survival. However, ovarian cancer–specific survival and overall survival were comparable among those with endometrioid, clear cell, and mucinous tumors. CONCLUSIONS Ovarian cancer remains the primary cause of death in long-term ovarian cancer survivors. Moreover, the probability of death was significantly different among those with different histological subtypes. It is important for clinicians to individualize the surveillance program for long-term ovarian cancer survivors.

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