Epithelial Ovarian Cancer Cases Research Articles

Moderate-Risk Genes for Hereditary Ovarian Cancers Involved in the Homologous Recombination Repair Pathway.

Approximately 20% of cases of epithelial ovarian cancer (EOC) are hereditary, sharing many causative genes with breast cancer. The lower frequency of EOC compared to breast cancer makes it challenging to estimate absolute or relative risk and verify the efficacy of risk-reducing surgery in individuals harboring germline pathogenic variants (GPV) in EOC predisposition genes, particularly those with relatively low penetrance. Here, we review the molecular features and hereditary tumor risk associated with several moderate-penetrance genes in EOC that are involved in the homologous recombination repair pathway, i.e., ATM, BRIP1, NBN, PALB2, and RAD51C/D. Understanding the molecular mechanisms underlying the expression and function of these genes may elucidate trends in the development and progression of hereditary tumors, including EOC. A fundamental understanding of the genes driving EOC can help us accurately estimate the genetic risk of developing EOC and select appropriate prevention and treatment strategies for hereditary EOC. Therefore, we summarize the functions of the candidate predisposition genes for EOC and discuss the clinical management of individuals carrying GPV in these genes.

Evaluation of promoter hypermethylation of tumor suppressor gene BRCA1 in epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is a serious gynecological issue worldwide and its late detection is the major encumbrance in treatment procedures. Hypermethylation-mediated BRCA1 gene silencing results in failure of the repair system of damaged DNA playing an important role in ovarian carcinogenesis. BRCA1 gene hypermethylation can serve as a safe and highly specific clinical marker for EOC. The present study was conducted to evaluate the promoter hypermethylation of BRCA1 gene in EOC patients. This hospital-based case-control study carried out in the tertiary care hospital in New Delhi. Subjects and Methods: Promoter hypermethylation of BRCA1 gene was examined in 30 EOC diagnosed untreated cases confirmed by histopathological examinations and compared with 30 normal healthy controls matched for age using methylation specific-polymerase chain reaction. We found significantly higher BRCA1 promoter hypermethylation in the serum of EOC cases as compared to controls with P < 0.0001. BRCA1 gene methylation was found to have 70% sensitivity for the diagnosis of EOC with 100% specificity. A significant difference was observed in the range of CA125 levels, B12 and Folate levels between EOC cases and controls. We conclude that BRCA1 gene is significantly hypermethylated in EOC patients and thus can prove to be a noninvasive diagnostic tool. Our results provide prefatory evidence that epithelial ovarian epigenome can be influenced by dietary nutrients.

Value of the risk of ovarian malignancy algorithm index in predicting the recurrence of epithelial ovarian cancer.

Aim: This study aimed to assess the predictive and diagnostic value of the risk of ovarian malignancy algorithm (ROMA) index for epithelial ovarian cancer (EOC) recurrence. Materials & methods: The clinical features and follow-up data of 159 EOC cases were studied. The ROMA indexwas calculated by serum CA125 andHE4 levels withmenopausal status. Recurrence-free survival was evaluated for an end point. Results: The ROMA was strongly associated with clinical characteristics. The ROMAindexabove the cutoff value (34.71%) was significantly associated with recurrence-free survival. The ROMA indexhad a significantly higher sensitivity (90.59%) than CA125 (84.71%) and HE4 (80.80%) for recurrence diagnosis, and its optimal cutoff value was 17.07%. Conclusion: The primary ROMA index is a predictive factor in EOC recurrence and has better performance in the diagnosis of EOC recurrence.

Effectiveness of Platinum-Based Chemotherapy after Progression on Poly ADP Ribose Polymerase (PARP) Inhibitor in Epithelial Ovarian Cancer (042)

<b>Objectives:</b> PARP inhibitors have revolutionized ovarian cancer care with dramatic improvements in progression-free (PFS) and overall survival when used as maintenance therapy following platinum-based treatment. However, much remains unknown about the response to subsequent treatment after progression on PARP inhibitor (PARPi) therapy, including whether a 6-month platinum-free interval is an appropriate benchmark for using a platinum-based regimen. Therefore, we aimed to assess response to platinum-based chemotherapy in women with platinum-sensitive recurrent epithelial ovarian cancer (EOC) after progression on PARPi. <b>Methods:</b> We performed a retrospective chart review of all cases of EOC prescribed a PARPi at a tertiary care center from 2015 to 2020. We included patients who progressed on PARPi and were subsequently treated with platinum-based chemotherapy. Patients who received fewer than six months of PARPi treatment were excluded. The primary outcome was PFS on the platinum regimen (ptPFS), defined as the time from the start of platinum therapy to physician documented progression. Germline and somatic <i>BRCA</i> testing, number of prior lines of chemotherapy, duration of therapy with PARPi and subsequent platinum regimen, and demographic data were collected for each case. An accelerated failure time model was developed to assess the primary outcome with a multivariable model including <i>BRCA</i> status, prior lines of chemotherapy, and time on PARPi in 6-month intervals. <b>Results:</b> A total of 283 charts were reviewed, and 40 cases met the inclusion criteria. Of these, 60% (<i>n</i>=24) had a <i>BRCA</i> mutation (<i>BRCA</i>mut); 75% (<i>n</i>=18) were germline and 25% (<i>n</i>=6) were somatic mutations. Twenty percent (<i>n</i>=8) of patients received a PARPi after first-line treatment, 45% (<i>n</i>=18) after second, 28% (<i>n</i>=11) after third, and 7% (<i>n</i>=3) after fourth. Sixty percent (<i>n</i>=24) of patients were prescribed olaparib, 20% (<i>n</i>=8) niraparib, 10% (<i>n</i>=4) rucaparib, and 10% received two agents due to toxicity with their first. The median time on PARPi was 411 days, and the median ptPFS was 218 days. In the multivariable model (Table 1), <i>BRCA</i> mutations were associated with decreased ptPFS (<i>BRCA</i>wt 274 days vs <i>BRCA</i>mut 170 days, p=0.004). The median time on PARPi greater than 18 months was associated with improved ptPFS compared to 12-18 months and <12 months (262 vs 188 vs 163 days, respectively, p=0.007). The number of prior lines of therapy was not associated with ptPFS (p=0.13). <b>Conclusions:</b> This retrospective analysis supports the ongoing use of platinum-based chemotherapy in recurrent EOC after progression on PARPi therapy with outcomes comparable to those seen in OCEANS and GOG-213. These data suggest that resistance to PARPi does not necessarily imply platinum resistance. Poorer ptPFS in tumors with a <i>BRCA</i>mut compared to those without was unexpected. While the data surrounding post PARPi treatment response is limited, growing evidence from the recently reported OReO trial corroborates this finding. This raises the question of a difference in the underlying mechanism leading to platinum resistance and PARPi resistance in <i>BRCA</i>mut versus <i>BRCA</i>wt EOC. Molecular assessment of recurrent tumors with clinical correlation will be important to optimize treatment approaches.

Frequency of homologous recombination deficiency in a large community-based cohort of epithelial ovarian cancer cases (597)

Frequency of homologous recombination deficiency in a large community-based cohort of epithelial ovarian cancer cases (597)

Development of an interactive precision medicine dashboard to aid in completion of germline and homologous recombination deficiency (HRD) tumor testing for newly diagnosed ovarian cancer patients to improve the use of PARP inhibitor frontline maintenance (583)

Development of an interactive precision medicine dashboard to aid in completion of germline and homologous recombination deficiency (HRD) tumor testing for newly diagnosed ovarian cancer patients to improve the use of PARP inhibitor frontline maintenance (583)

Adverse Events Associated With Long-term Treatment of Epithelial Ovarian Cancer With Bevacizumab and Chemotherapy.

Adverse events associated with long-term bevacizumab administration for ovarian cancer have been poorly documented in Japan. This study aimed to evaluate the adverse events of bevacizumab combined with chemotherapy for treating primary and recurrent epithelial ovarian cancer in Japan. In this single-center retrospective study, we analyzed data of patients with advanced and recurrent epithelial ovarian cancer treated with bevacizumab and chemotherapy between January 2013 and November 2019. Statistical analyses were performed using the Fisher's exact test and Kaplan-Meier method. A total of 46 patients were included and the follow-up time was 30 months. The median duration of bevacizumab treatment was 14 months, and the median total dose of bevacizumab was 247.5 mg/kg. The most common adverse events were hypertension (n=30; 65.2%) and proteinuria (n=24; 49%) in all grades. The onset of hypertension and proteinuria occurred at a median of 2 months and 14 months after treatment initiation in all grades, respectively. Gastrointestinal perforation occurred significantly more frequently in patients with a history of radiation therapy. This study included cases of primary advanced and recurrent epithelial ovarian cancer, and had a longer observation period and reported more adverse events of bevacizumab with chemotherapy than previous reports. The administration of bevacizumab therapy in patients with a history of radiation should be carefully considered due to increased chances of gastrointestinal perforation.

Abstract 736: Exploring the impact of infertility and its treatments on risk of ovarian cancer

Abstract Background: Infertility is related to both nulligravidity and endometriosis, which are both well-established risk factors for ovarian cancer. Infertility is also characterized by various underlying causes and can be treated with different types of fertility drugs. However, most studies to date have been unable to properly address these important issues when examining the infertility-ovarian cancer association due to small numbers of patients and a lack of detailed infertility and risk factor information. Methods: We pooled self-reported data from 8,324 invasive, epithelial ovarian cancer cases and 13,325 control women in eight population-based case-control studies participating in the Ovarian Cancer Association Consortium (OCAC) to study the infertility-ovarian cancer relationship. Women classified as having a history of infertility were those who had spoken to a doctor about infertility problems or those who had regular sexual intercourse without birth control for a prolonged period (usually one year) without getting pregnant. Cause of infertility as well as use of fertility drugs was examined among those who experienced infertility issues. These associations with risk of ovarian cancer were evaluated using logistic regression models and quantified using odds ratios (ORs) and 95% confidence intervals (CIs). Gravidity and endometriosis were considered in the analyses as well as potential confounding factors. Results: Overall, infertility was not associated with risk of ovarian cancer (OR=1.02, 95% CI 0.95-1.09). However, women who reported their infertility was due to problems with ovulation or menstruation showed a decreased risk (OR=0.72, 95% CI 0.52-1.01 and OR=0.62, 95% CI 0.43-0.91, respectively) whereas women who reported their infertility was due to endometriosis were at an increased risk (OR=1.54, 95% CI 1.19-1.98). Among women who reported infertility issues, use of fertility drugs was not associated with an increased risk of ovarian cancer regardless of their gravidity status (OR=0.89, 95% CI 0.76-1.05). Conclusions: The relationship between infertility and risk of ovarian cancer is complex. Although infertility does not appear to be an independent risk factor for ovarian cancer, specific causes of infertility may be differentially associated with ovarian cancer risk, which may shed light on the disease’s underlying etiology. In addition, for women experiencing infertility issues, use of fertility drugs did not show an increased risk of ovarian cancer, which may have important clinical implications. Citation Format: Alice W. Lee, Minh T. Phung, Allan Jensen, Anna H. Wu, Daniel W. Cramer, Francesmary Modugno, Holly Harris, Jennifer A. Doherty, Joellen Schildkraut, Kathryn L. Terry, Kirsten B. Moysich, Malcolm C. Pike, Marc T. Goodman, Penelope M. Webb, Susanne K. Kjaer, Celeste L. Pearce. Exploring the impact of infertility and its treatments on risk of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 736.

Abstract 30: A pedigree-based approach to ovarian cancer risk variant discovery in the Utah Population Database

Abstract Introduction: Genetic risk variants are critical to risk prediction for invasive epithelial ovarian cancer (EOC), yet an estimated 50-55% of EOC heritability remains missing. Novel approaches to risk variant discovery are needed to detect variants that have not been uncovered by linkage analysis or genome-wide association studies (GWAS). We approach risk variant discovery using Shared Genomic Segment analysis (SGS), a novel statistical genetics method that enables risk variant discovery in extended high-risk pedigrees. Methods: The Utah Population Database (UPDB) is a population-based resource of over ten million individuals connected to the state of Utah, five million of whom are linked to a minimum of three generations of genealogy data. By linking this genealogy data with cancer data from the Utah Cancer Registry, we identified pedigrees with an excess risk of EOC. We generated germline genotyping data from cases (diagnosed 1983-2018) in a subset of these high-risk pedigrees, focusing on pedigrees well-suited for SGS (i.e., at least 3 cases separated by a total of at least 12 meioses). SGS identifies all runs of consecutive alleles that are shared identical-by-state by cases in a pedigree and determines which of these genomic segments are longer than would be expected by chance. These long segments are likely to be identical-by-descent, inherited from a common founder, and may harbor risk variants. Results: We successfully linked UPDB genealogy data to information from the Utah Cancer Registry to identify approximately 2,000 extended high-risk pedigrees with ≥5 ovarian cancer cases, an average of 7-10 meioses between pairs cases, and a statistically significant excess risk of ovarian cancer (α=0.05). We obtained biospecimens for 141 cases in 36 of the most promising pedigrees (i.e., high familial standardized incidence ratio, p-value&amp;lt;0.005, not attributable to known risk variants in BRCA1 or BRCA2 as observed in first-, second- or third-degree relatives of EOC cases). We genotyped 96 out of the 141 cases in these pedigrees (68%). SGS analyses to identify genomic regions that may harbor risk variants are currently underway. Conclusions: Using pedigrees identified in the UPBD, SGS has identified risk loci and novel risk variants for a number of diseases, including breast and hematologic cancers. We have identified a set of EOC high-risk pedigrees for SGS analysis and will leverage SGS to identify genomic regions that may harbor EOC risk variants. Citation Format: Mollie E. Barnard, Robert Sargent, G. Bryce Christensen, Bonita A. Mahaffey, James Albro, Elke A. Jarboe, Terence Rhodes, Nicola J. Camp, Jennifer A. Doherty. A pedigree-based approach to ovarian cancer risk variant discovery in the Utah Population Database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 30.

Familial risk of epithelial ovarian cancer after accounting for gynaecological surgery: a population-based study

BackgroundUptake of risk-reducing surgery has increased among women at high risk of epithelial ovarian cancer. We sought to characterise familial risk of epithelial ovarian cancer histotypes in a population-based study...

DNA Repair of Ovarian Cancer Cell Lines SKOV3 and OV90 Compared to Non‐Transformed PBMC Cells

A defining characteristic of cancer is the increase in genomic instability along with the progression of carcinogenesis, in which DNA mutations are the biggest contributors. Further, most mutations related to the development of ovarian cancer are acquired instead of inherited, demonstrating that familial tumors are the minority of cases. Two ovarian cancer cell lines that are extensively used in research are OV‐90 and SK‐OV‐3. We used the comet assay (single‐cell gel electrophoresis) to quantify DNA repair abilities in these cell lines compared to PBMCs (peripheral blood mononuclear cells), in order to assess the sensitivity of these cell lines to radiation treatments. A difference in DNA repair ability is expected in the cell lines compared to PBMCs due to the genomic instability related to tumorigenesis. After being treated with X‐ray radiation and undergoing a designated repair time, individual cells were scored, using fluorescent microscopy, based on percent “head” and “tail” DNA. It appears that SK‐OV‐3 is repairing DNA faster than PBMC, while OV‐90 repairs DNA more similarly to PBMCs. This observation has important implications for the development of drugs to treat ovarian cancer, along with understanding the dynamics of DNA repair within cancer cells. Considering that most cases of epithelial ovarian cancer remain death sentences in spite of new treatments, insights regarding cell line sensitivity are of even more importance with every passing day.

Algorithm to Identify Incident Epithelial Ovarian Cancer Cases Using Claims Data.

To create an algorithm to identify incident epithelial ovarian cancer cases in claims-based data sets and evaluate performance of the algorithm using SEER-Medicare claims data. We created a five-step algorithm on the basis of clinical expertise to identify incident epithelial ovarian cancer cases using claims data for (1) ovarian cancer diagnosis, (2) receipt of platinum-based chemotherapy, (3) no claim for platinum-based chemotherapy but claim for tumor debulking surgery, (4) removed cases with nonplatinum chemotherapy, and (5) removed patients with prior claims with personal history of ovarian cancer code to exclude prevalent cases. We evaluated algorithm performance using SEER-Medicare claims data by creating four cohorts: incident epithelial ovarian cancer, a 5% random sample of cancer-free Medicare beneficiaries, a 5% random sample of incident nonovarian cancer, and prevalent ovarian cancer cases. Using SEER tumor registry data as the gold standard, our algorithm correctly classified 89.9% of incident epithelial ovarian cancer cases (cohort n = 572) and almost 100% of cancer-free controls (n = 97,127), nonovarian cancer (n = 714), and prevalent ovarian cancer cases (n = 3,712). The overall algorithm sensitivity was 89.9%, the positive predictive value was 93.8%, and the specificity and negative predictive value were > 99.9%. Patients were more likely to be correctly classified as incident ovarian cancer if they had stage III or IV disease compared with early stage I or II disease (93.5% v 83.7%, P < .01), and grade 1-4 compared with unknown grade tumors (93.8% v 81.4%, P < .01). Our algorithm correctly identified most incident epithelial ovarian cancer cases, especially those with advanced disease. This algorithm will facilitate research in other claims-based data sets where cancer registry data are unavailable.

BRCA1/2 in non-mucinous epithelial ovarian cancer: tumour with or without germline testing?

National guidelines recommend testing all cases of non-mucinous epithelial ovarian cancer (NMEOC) for germline (blood) and somatic (tumour) BRCA1/2 pathogenic variants (PVs). We performed paired germline and somatic BRCA1/2 testing in consecutive cases of NMEOC (n = 388) to validate guidelines. Thirty-four somatic BRCA1/2 (sBRCA) PVs (9.7%) were detected in 350 cases with germline BRCA1/2 (gBRCA) wild-type. All sBRCA PVs were detected in non-familial cases. By analysing our regional germline BRCA1/2 database there were 92/1114 (8.3%) gBRCA PVs detected in non-familial cases (only 3% ≥70 years old) and 245/641 (38.2%) in familial cases. Germline non-familial cases were dominated by BRCA2 in older women (8/271 ≥ 70 years old, all BRCA2). The ratio of sBRCA-to-gBRCA was ≤1.0 in women aged <70 years old, compared to 5.2 in women aged ≥70 years old (P = 0.005). The likelihood of missed germline BRCA1/2 PVs (copy-number variants missed on most somatic assays) by testing only tumour DNA was 0.4% in women aged ≥70 years old. We recommend reflex tumour BRCA1/2 testing in all NMEOC cases, and that gBRCA testing is not required for women aged ≥70 years old with no identifiable tumour BRCA1/2 PV and/or family history of breast, ovarian, prostate and/or pancreatic cancer.

Endocan-microvascular Density in Primary Ovarian Carcinoma.

Background:Epithelial ovarian cancer is among the leading causes of death in women and is driven by angiogenesis. Microvascular density (MVD) can be used to evaluate angiogenesis in carcinomas and thus it can be used as a potential biomarker for ovarian cancer. This study is aimed to establish the association between endocan-MVD with clinicopathological factors in primary epithelial ovarian cancer. Methods:The clinicopathological characteristics were acquired from the medical records filed between January 2008 and December 2018 of 89 epithelial ovarian cancer cases in Hospital Universiti Sains Malaysia, Kelantan, Malaysia. Sectioned samples were analyzed for endocan through immunohistochemistry followed by the quantification of MVD. The association between clinicopathological characteristics and endocan-MVD was analyzed using the Pearson chi-square test and Fischer’s exact test. Results:All cases of epithelial ovarian carcinomas were positive for endocan. The mean ± standard deviation value of endocan-MVD level was 21.6±14.60 microvessels per 200x field. A total of 53 (59.6%) cases had low and 36 (40.04%) had high endocan-MVD values. High endocan-MVD level had a significant association with the older age group (p-value = 0.009), smaller tumor size (p-value<0.001), type II tumor (p-value<0.001), high-grade tumor (p-value<0.001), advanced FIGO stage (p-value=0.002), and presence of tumor recurrence (p-value=0.017). No significant association was found between endocan-MVD and the other clinicopathological characteristics such as race, pre-operative serum CA-125 level, presence of diabetes mellitus, endometriosis, lymph node involvement, distant metastasis, and family history of malignancy. Conclusion:Endocan-MVD showed a significant association with age, tumor size, tumor type, tumor grade, FIGO stage, and recurrence in primary epithelial ovarian cancer. Thus, endocan-MVD could be implemented as a reliable marker to predict prognosis in epithelial ovarian cancer in the future.

Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28–1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08–1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21–1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29–1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35–1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

Plasma circN4BP2L2 is a promising novel diagnostic biomarker for epithelial ovarian cancer

BackgroundCircular RNAs (circRNAs) are more stable than linear RNA molecules, which makes them promising diagnostic biomarkers for diseases. By circRNA-sequencing analysis, we previously found that circN4BP2L2 was significantly decreased in epithelial ovarian cancer (EOC) tissues, and was predictive of disease progression. The aim of this study was to evaluate the diagnostic value of plasma circN4BP2L2 in EOC.MethodsThree hundred seventy-eight plasma samples were acquired prior to surgery. Samples were obtained from 126 EOC patients, 126 benign ovarian cyst patients, and 126 healthy volunteers. CircN4BP2L2 was assessed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) were assessed using enzyme-linked immunosorbent assay (ELISA). EOC cells were transfected with small interference RNAs (siRNAs) and cell proliferation, migration, invasion, cell cycle and cell apoptosis were performed to assess the effect of circN4BP2L2 in EOC. Receiver operating curve (ROC), the area under the curve (AUC), sensitivity and specificity were estimated.ResultsPlasma circN4BP2L2 was significantly downregulated in EOC patients. Decreased circN4BP2L2 was significantly associated with advanced tumor stage, worse histological grade, lymph node metastasis and distant metastasis in EOC. CircN4BP2L2 inhibited tumor cell migration and invasion in vitro. CircN4BP2L2 could significantly separate EOC from benign (AUC = 0.82, P < 0.01) or normal (AUC = 0.90, P < 0.01) cohort. Early stage EOC vs benign (AUC = 0.81, P < 0.01) or normal (AUC = 0.90, P < 0.01) cohort could also be distinguished by circN4BP2L2. In discrimination between EOC cohort and benign or normal cohort, circN4BP2L2 performed equally well in both pre- and post-menopausal women. The combination of circN4BP2L2, CA125 and HE4 showed high sensitivity and specificity in detecting EOC cases.ConclusionsPlasma circN4BP2L2 is significantly downregulated in EOC and might serve as a promising novel diagnostic biomarker for EOC patients, especially in early stage EOC cases. CircN4BP2L2 might act as an adjunct to CA125 and HE4 in detecting EOC. Further large-scale studies are warranted to verify our results.

Cause-specific mortality rate of ovarian cancer in the presence of competing risks of death: a nationwide population-based cohort study.

ObjectiveThis nationwide cohort study aimed to evaluate the cause-specific mortality (probability of death by ovarian cancer, probability of death by other causes) under the competing risks of death in women with ovarian cancer.MethodsThe Korea Central Cancer Registry was searched to identify women with primary ovarian cancer diagnosed between 2006 and 2016. Epithelial ovarian cancer cases were identified using the International Classification of Diseases for Oncology 3rd edition. We estimated the cause-specific mortality according to age (<65 years, ≥65 years), stage (local, regional, and distant), and histology (serous, mucinous, endometrioid, clear cell, and others) under the competing risks framework; moreover, cumulative incidences were estimated.ResultsWe included 21,446 cases. Cause-specific mortality continuously increased throughout 10 year follow-up. Compared with women aged <65 years, ovarian cancer-specific mortality (5-year, 28.9% vs. 61.9%; 10-year, 39.0% vs. 68.6%, p<0.001) and other cause mortality (5-year, 1.7% vs. 4.8%; 10-year, 2.8% vs. 8.2%, p<0.001) increased in women aged ≥65 years. This trend was consistent across all the stages and histological types. There was a substantial increase in competing risks from 1.1% in women aged <65 years to 8.0% in women aged ≥65 years in patients with early-stage (p<0.001) non-serous ovarian cancer (p<0.001).ConclusionOlder age at diagnosis is associated with increasing ovarian cancer-specific mortality and competing risks. Given the substantial effect of competing risks on elderly patients, there is a need for assessment tools to balance the beneficial and harmful effects to provide optimal treatment.

STAT1-Induced Upregulation lncRNA LINC00958 Accelerates the Epithelial Ovarian Cancer Tumorigenesis by Regulating Wnt/β-Catenin Signaling.

Background Growing studies have demonstrated that long noncoding RNAs (lncRNAs) play important roles in tumor progression. In this study, we aimed to explore the potential roles of lncRNA LINC00958 (LINC00958) and its biological functions in epithelial ovarian cancer (EOC). Methods The expression of LINC00958 in 11 cases of EOC and adjacent nontumor specimens and five cell lines was detected by qRT-PCR. CCK-8, colony formation, and flow cytometry assays were conducted to study the cell viabilities of EOC cells. Wound scratch and transwell analyses were carried out for the examination of cell invasion and migration of EOC cells. The targeting associations between LINC00958 and STAT1 were demonstrated by ChIP analyses combined with luciferase reporter assays. The related proteins of Wnt/β-catenin signaling were determined using RT-PCR. Results Higher levels of LINC00958 were observed in EOC tissues and cell lines. Our data also revealed that high LINC00958 expression was partly induced by STAT1. Functionally, knockdown of LINC00958 suppressed the proliferation, migration, and invasion of EOC cells. Mechanistic investigation showed that the inhibitory effect of LINC00958 knockdown on EOC cells was mediated by the Wnt/β-catenin signaling. Conclusion Our findings suggested that STAT1-induced overexpression of LINC00958 promoted EOC progression by modulating Wnt/β-catenin signaling.

Prognostic value of preoperative soluble interleukin 2 receptor α as a novel immune biomarker in epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is regarded as the deadliest gynecological cancer, and the demand for novel noninvasive prognostic biomarkers remains significant. This study aimed to investigate the prognostic value of preoperative blood biomarkers in EOC patients. In total, 73 patients who had undergone ovarian mass resection were enrolled. Serum concentration of biomarkers, including soluble interleukin 2 receptor α (sIL-2R), was measured 1-2weeks before surgery. Independent prognostic factors for progression-free survival (PFS) were investigated with multivariate Cox regression analysis. A prognostic model was subsequently developed and evaluated by discrimination, calibration and clinical net benefit. Furthermore, transcriptome data of 376 EOC cases from The Cancer Genome Atlas (TCGA) were analyzed with ESTIMATE, CIBERSORT and Maftools algorithm to evaluate the correlation of IL2RA expression with tumor immune microenvironment and immunotherapeutic response. High sIL-2R concentration was found to be the only significant prognostic blood biomarker for PFS by multivariate Cox regression analysis in our center. A prognostic nomogram was developed with satisfactory discrimination, calibration and clinical net benefit. In addition, higher IL2RA expression was significantly associated with higher immune scores, activated CD4+ T cells, M2 macrophages and resting dendritic cells in TCGA data. Furthermore, IL2RA expression was closely related to TMB scores. sIL-2R is a potential prognostic immune biomarker for EOC patients, and a comprehensive prognostic model comprising sIL-2R with satisfactory discrimination and clinical appliance was developed. Therefore, we recommend routine sIL-2R testing in EOC patients.

Observational study on serum markers and circulating tumor cells in ovarian cancer

1) To detect Cyclophilin, APC and SFRP5 genes associated with Epithelial ovarian cancer by PCR. 2) To study and compare the prognostic and diagnostic efficacy of serological markers like Ca 125 and HE4 and their correlation with epithelial/ non epithelial ovarian neoplasms.Comparative observational study, Prospective study 64 cases fulfilling the inclusion criteria and giving their consent for inclusion in the study were enrolled as subjects of the present study over a period of one year. After DNA extraction (Invitrogen mini kit, USA) conventional PCR to amplify the extracted DNA and further subjected them to agarose gel electrophoresis for the identification(expression) of 3 genes i.e Cyclophillin, APC and SFRP5, was done; However, none expressed.ELISA was used to assess CA125 and HE4 pre and post surgical intervention. The serum markers were raised more in malignant epithelial ovarian cancer cases and levels plummeted after surgical intervention, as compared to benign masses. We could not establish correlation of the genes’ expression with the serum markers and histopathology. Combining HE4 and CA125 both might be more helpful than either of them using alone, in diagnosing as well as prognosticating ovarian diseases. A panel of multiple genes on a larger sample size may be needed for CTC detection.Early detection of ovarian tumors leads to early diagnosis and hence early institution of intervention and hence decreased morbidity and mortality.