Cystadenocarcinoma Patients Research Articles

Significant age cutoff of 73 years for advanced ovarian serous cystadenocarcinoma patients: Insights from real-world study

Significant age cutoff of 73 years for advanced ovarian serous cystadenocarcinoma patients: Insights from real-world study

Significant Prognostic Factor at Age Cut-off of 73 Years for Advanced Ovarian Serous Cystadenocarcinoma Patients: Insights from Real-World Study

Significant Prognostic Factor at Age Cut-off of 73 Years for Advanced Ovarian Serous Cystadenocarcinoma Patients: Insights from Real-World Study

Expression Profiles of ID and E2A in Ovarian Cancer and Suppression of Ovarian Cancer by the E2A Isoform E47.

Simple SummaryOvarian cancer is one of the most fatal gynecological malignancies in women. Even though primary treatment might result in complete remission, approximately 60–80% patients with advanced-stage ovarian cancer experience a relapse. To improve their survival outcomes, several novel agents have been proposed; however, the majority of these have demonstrated limited efficacy in the treatment of ovarian cancer. Interestingly, an imbalance in the basic helix-loop-helix inhibitor of DNA binding (bHLH/ID) protein networks has been associated with oncogenesis, but the exact expression patterns of bHLH/ID in ovarian cancer are not yet known. We hypothesized that such an imbalance in bHLH/ID activity may be integral to ovarian cancer pathogenesis, and modulating the bHLH/ID balance might be a promising approach to treat ovarian cancer.The E2A and inhibitor of DNA binding (ID) proteins are transcription factors involved in cell cycle regulation and cellular differentiation. Imbalance of ID/E2A activity is associated with oncogenesis in various tumors, but their expression patterns and prognostic values are still unknown. We evaluated ID and E2A expression in ovarian cancer cells, and assessed the possibility of reprogramming ovarian cellular homeostasis by restoring the ID/E2A axis. We analyzed copy number alterations, mutations, methylations, and mRNA expressions of ID 1–4 and E2A using The Cancer Genome Atlas data of 570 ovarian serous cystadenocarcinoma patients. Incidentally, 97.2% cases exhibited gain of ID 1–4 or loss of E2A. Predominantly, ID 1–4 were hypomethylated, while E2A was hypermethylated. Immunohistochemical analysis revealed that ID-3 and ID-4 expressions were high while E2A expression was low in cancerous ovarian tissues. Correlation analysis of ID and E2A levels with survival outcomes of ovarian cancer patients indicated that patients with high ID-3 levels had poor overall survival. We also determined the effect of E2A induction on ovarian cancer cell growth in vitro and in vivo using SKOV-3/Luc cells transduced with tamoxifen-inducible E47, a splice variant of E2A. Interestingly, E47 induced SKOV-3 cell death in vitro and inhibited tumor growth in SKOV-3 implanted mice. Therefore, restoring ID/E2A balance is a promising approach for treating ovarian cancer.

Combination of Immune-Related Genomic Alterations Reveals Immune Characterization and Prediction of Different Prognostic Risks in Ovarian Cancer.

With the highest case-fatality rate among women, the molecular pathological alterations of ovarian cancer (OV) are complex, depending on the diversity of genomic alterations. Increasing evidence supports that immune infiltration in tumors is associated with prognosis. Therefore, we aim to assess infiltration in OV using multiple methods to capture genomic signatures regulating immune events to identify reliable predictions of different outcomes. A dataset of 309 ovarian serous cystadenocarcinoma patients with overall survival >90 days from The Cancer Genome Atlas (TCGA) was analyzed. Multiple estimations and clustering methods identified and verified two immune clusters with component differences. Functional analyses pointed out immune-related alterations underlying internal genomic variables potentially. After extracting immune genes from a public database, the LASSO Cox regression model with 10-fold cross-validation was used for selecting genes associated with overall survival rate significantly, and a risk score model was then constructed. Kaplan–Meier survival and Cox regression analyses among cohorts were performed systematically to evaluate prognostic efficiency among the risk score model and other clinical pathological parameters, establishing a predictive ability independently. Furthermore, this risk score model was compared among identified signatures in previous studies and applied to two external cohorts, showing better prediction performance and generalization ability, and also validated as robust in association with immune cell infiltration in bulk tissues. Besides, a transcription factor regulation network suggested upper regulatory mechanisms in OV. Our immune risk score model may provide gyneco-oncologists with predictive values for the prognosis and treatment management of patients with OV.

Dynamic TF-lncRNA Regulatory Networks Revealed Prognostic Signatures in the Development of Ovarian Cancer.

The pathological development of ovarian cancer (OC) is a complex progression that depends on multiple alterations of coding and non-coding genes. Therefore, it is important to capture the transcriptional-regulating events during the progression of OC development and to identify reliable markers for predicting clinical outcomes in patients. A dataset of 399 ovarian serous cystadenocarcinoma patients at different stages from The Cancer Genome Atlas (TCGA) was analyzed. Stage-specific transcription factor (TF)-long non-coding RNA (lncRNA) regulatory networks were constructed by integrating high-throughput RNA molecular profiles and TF binding information. Systematic analysis was performed to characterize the TF-lncRNA-regulating behaviors across different stages of OC. Cox regression analysis and Kaplan-Meier survival curves were used to evaluate the prognostic efficiency of TF-lncRNA regulations and cliques. The stage-specific TF-lncRNA regulatory networks at three OC stages (II, III, and IV) exhibited common structures and specific topologies of risk TFs and lncRNAs. A TF-lncRNA activity profile across different stages revealed that TFs were highly stage-selective in regulating lncRNAs. Functional analysis indicated that groups of TF-lncRNA interactions were involved in specific pathological processes in the development of OC. In a STAT3-FOS co-regulating clique, the TFs STAT3 and FOS were selectively regulating target lncRNAs across different OC stages. Further survival analysis indicated that this TF-lncRNA biclique may have the potential for predicting OC prognosis. This study revealed the topological and dynamic principles of TF-lncRNA regulatory networks and provided a resource for further analysis of stage-specific regulating mechanisms of OC.

Abstract 4358: Landscape of allelic imbalance in pan-cancer adjacent normal tissue: Insights into field cancerization and cancer pathogenesis

Abstract It has been observed that tumors and adjacent normal appearing tissues share molecular signatures. This phenomenon has been observed in tissues of the skin, colon, and lung among others, particularly for patterns of gene expression. A recent pan cancer study of gene expression in normal tissue adjacent to the tumor (NAT) has shown that NATs have unique expression profiles that are distinct from non-tumor-bearing tissues. In this work, we sought to further characterize the molecular profile of NAT samples across cancer types. We have previously applied our haplotype based statistical technique to survey allelic imbalance (AI) in putatively normal lung tissues adjacent to tumor. Using this method, we can detect changes indicative of chromosomal alteration (gain, loss and copy-neutral LOH) even when present at low mutant cell fractions (< 5%). We focused our analysis on a subset of TCGA patients with both a solid tumor and NAT sample (n = 1530). In addition, to serve as a control, we surveyed alterations in normal samples derived from blood (n = 7,796). We detected 218 (megabase scale) chromosomal alterations in 44 of the NAT samples. These somatic alterations were present at a higher rate in NAT (2.9%) compared to the control normal blood set (1.9%). NAT samples with detectable AI had an average of 5 AI events compared to an average of 2 events in blood samples. We did not detect AI in the blood samples from the 44 patients with AI in the NAT. The most common recurrent alterations in NAT were 8p23.1, 17q21.31 and 1q42.12-1q42.13; each found in 14% of NAT AI positive samples. Chromosomal alterations in NAT were present at different rates between cancer types. We detected AI in more than 10% of NATs from breast invasive carcinoma, sarcoma, and bladder urothelial carcinoma. Of the 218 AI events in NAT, 67% were detected in the matching tumor sample. Two cancers, kidney renal papillary cell carcinoma and thyroid carcinoma, had a positive correlation between presence of AI in NAT and AI burden in the matched tumor sample (P = 0.005 and 0.03 respectively). The most common mutations in the tumors of patients with chromosomal aberrations in NAT were TP53 and MUC16 found in 39% and 20%, of tumors respectively. Lung squamous carcinoma and ovarian serous cystadenocarcinoma patients with detectable AI in NAT had a worse survival rate (P = 0.0241 and 0.0439 respectively). Our survey of AI in NAT tissues provides further support for NAT tissues as a model for understanding cancer pathogenesis. Citation Format: Yasminka A. Jakubek, Francis A. San Lucas, Smruthy Sivakumar, Richard G. Fowler, Humam Kadara, Paul Scheet. Landscape of allelic imbalance in pan-cancer adjacent normal tissue: Insights into field cancerization and cancer pathogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4358.

MiR-744-5p inducing cell death by directly targeting HNRNPC and NFIX in ovarian cancer cells

MicroRNAs (miRNAs) play an important role in the regulation of gene expression. The binding to target messenger RNAs (mRNAs) results in mRNA cleavage or inhibition of the translational machinery leading to decreased protein levels. Various signalling pathways, including apoptosis are modulated by miRNAs. Here, we investigated the role of miR-744-5p in apoptosis signalling in ovarian cancer cell lines. MiR-744-5p expression was reduced in the cancer cell lines independent of the host gene MAP2K4. Overexpression of miR-744-5p activated the intrinsic apoptotic pathway in SKOV3, OVCAR3 and Cisplatin resistant (A2780-cis) and non-resistant A2780 cells leading to cell death. Notably, miR-744-5p overexpression together with Carboplatin treatment led to at least additive pro-apoptotic effects. Investigation of the apoptotic signalling pathways mediated by miR-744-5p revealed that its elevated expression directly downregulated mRNA and protein expression of nuclear factor I X (NFIX) and heterogeneous nuclear ribonucleoprotein C (HNRNPC). HNRNPC caused diminished miR-21 expression and AKT phosphorylation, while NFIX decreased Bcl2 levels, leading to the detected pro-apoptotic effects. Finally, Kaplan-Meier-Plots showed a prolonged median disease-free survival in ovarian serous cystadenocarcinoma patients with high miR-744 expression.

Abstract 2249: Integrated multi-level omics-based biomarker models for ovarian cancer survival

Abstract Background: Although a number of prognostic biomarkers for ovarian cancer have been proposed, the pool of clinically useful biomarkers remains small. While the predictive power of individual biomarkers may be weak, the advent of more affordable high-throughput technologies and readily available “omics” level data point toward the possibility of high performance biomarker panels. In this study, we used tumor-based somatic mutation, mRNA and miRNA expression, and DNA methylation data from The Cancer Genome Atlas (TCGA) to construct integrated biomarker models for overall and progression-free survival. Methods: The somatic mutations, mRNA expression, and DNA methylation of 451 candidate genes, as well as the expression of the miRNAs targeting them, were individually analyzed for association with overall and progression-free survival in 488 TCGA serous cystadenocarcinoma patients of predominantly Caucasian descent. Following correction for multiple comparisons, molecular variations associated with survival were combined to construct integrated cross-validated prediction models for overall and progression-free survival. The discriminative power of these models was then evaluated for 1-, 3-, and 5-year overall and progression-free survival using ROC analysis. Results: Our cross-validated integrated molecular models were demonstrated to predict 5-year overall survival in the total patient pool with a ROC AUC of 0.801 and 5-year overall and progression-free survival in Caucasian patients with ROC AUCs of 0.866 and 0.809, respectively. Conclusions: Our findings suggest the potential utility of our multi-omics-based biomarker models in helping to inform clinical decisions following ovarian cancer diagnosis. Although extensive efforts were made to maximize the predictive potential of our models, further retrospective and prospective validation efforts are necessary before their clinical utility can be accurately assessed. Citation Format: Alan Fu, Shen-Chih Chang, Aileen Baecker, Helena R. Chang, Zuo-Feng Zhang. Integrated multi-level omics-based biomarker models for ovarian cancer survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2249. doi:10.1158/1538-7445.AM2017-2249

Characteristics and outcomes of resected pancreatic cystadenocarcinoma: 1,205 cases from the National Cancer Data Base.

4129 Background: Cystadenocarcinoma (CAC) of the pancreas is a rare pancreatic and therefore there is limited data on the characteristics, treatment and prognosis of this disease. Methods: Patients who underwent resection for CAC (n = 1,205) between 2003 and 2012 were identified from National Cancer Data Base. The clinicopathological characteristics and treatment outcomes were compared to patients with resected ductal adenocarcinoma (DAC) (n = 15,696). Cox-proportional hazard model was used to adjust for potential prognostic factors. A nomogram was constructed and validated to predict the outcomes of patients with CAC by using multiple variable Cox-proportional model and receiver operating characteristics curve methods. Results: Compared with resected DAC, patients with resected CAC are diagnosed at a younger age (58.7 vs. 61.2, p < 0.0001); female predominant (63.7% vs. 48.8%, p < 0.0001); more often Black (15.0% vs. 9.3%, p < 0.0001);had larger tumor (0-2, 2-4 and > 4cm:17.5%, 24.3%, 53.5% vs. 16.8%, 48.3% , 32.1%, respectively, p < 0.0001); have less total number of examined lymph nodes (10.6 vs. 14.5, p < 0.0001) and fewer positive lymph nodes(0.6 vs. 2.3, respectively). CAC patients were less likely to receive chemotherapy (28.8% vs. 62.5%, p < 0.0001) and radiation therapy (16.4% vs. 36.9%, p < 0.0001). CAC patients had significantly better overall survival than those with DAC (5 year survival: 55.6% vs. 17.3%, p < 0.0001). The survival advantage was primarily seen in patients with early stage disease (5 year survival: 70.9% vs. 36.9% in stage I patients, p < 0.0001, and 32.7% vs. 14.5% in stage II patients, p < 0.0001 respectively) and persisted after adjusting the known prognostic factors including age, AJCC staging, Charlson-Deyo score, type of surgery, chemotherapy, tumor size, and lymph node ratio (adjusted hazard ratio: 0.43, 95% confidence interval: 0.39-0.48, p < 0.0001). Conclusions: Patients with CAC had significantly better survival than those with pancreatic DAC even after controlling for known prognostic factors. The proposed nomogram could accurately predict patients’ outcome and may be used as a tool for clinical decision making.

A DNA Repair Pathway–Focused Score for Prediction of Outcomes in Ovarian Cancer Treated With Platinum-Based Chemotherapy

BackgroundNew tools are needed to predict outcomes of ovarian cancer patients treated with platinum-based chemotherapy. We hypothesized that a molecular score based on expression of genes that are involved in platinum-induced DNA damage repair could provide such prognostic information.MethodsGene expression data was extracted from The Cancer Genome Atlas (TCGA) database for 151 DNA repair genes from tumors of serous ovarian cystadenocarcinoma patients (n = 511). A molecular score was generated based on the expression of 23 genes involved in platinum-induced DNA damage repair pathways. Patients were divided into low (scores 0–10) and high (scores 11–20) score groups, and overall survival (OS) was analyzed by Kaplan–Meier method. Results were validated in two gene expression microarray datasets. Association of the score with OS was compared with known clinical factors (age, stage, grade, and extent of surgical debulking) using univariate and multivariable Cox proportional hazards models. Score performance was evaluated by receiver operating characteristic (ROC) curve analysis. Correlations between the score and likelihood of complete response, recurrence-free survival, and progression-free survival were assessed. Statistical tests were two-sided.ResultsImproved survival was associated with being in the high-scoring group (high vs low scores: 5-year OS, 40% vs 17%, P < .001), and results were reproduced in the validation datasets (P < .05). The score was the only pretreatment factor that showed a statistically significant association with OS (high vs low scores, hazard ratio of death = 0.40, 95% confidence interval = 0.32 to 0.66, P < .001). ROC curves indicated that the score outperformed the known clinical factors (score in a validation dataset vs clinical factors, area under the curve = 0.65 vs 0.52). The score positively correlated with complete response rate, recurrence-free survival, and progression-free survival (Pearson correlation coefficient [r2] = 0.60, 0.84, and 0.80, respectively; P < .001 for all).ConclusionThe DNA repair pathway–focused score can be used to predict outcomes and response to platinum therapy in ovarian cancer patients.

Radical resection and outcome for malignant tumors of thepancreatic body and tail

To analyze the factors influencing radical (R0) resection rate and surgical outcome for malignant tumor of the pancreatic body and tail. The clinical and operative data and follow-up results of 214 pancreatic body and tail cancer patients were analyzed retrospectively. One hundred and twenty/214 pancreatic body and tail cancer patients underwent surgical treatment; the overall resection rate was 59.2% (71/120), and the R0 resection rate was 40.8% (49/120). Compared with non-R0 treatment, the patients receiving an R0 resection had smaller size tumor (P<0.01), cystadenocarcinoma (P<0.01), less lymph node metastasis (P<0.01), less peri-pancreatic organ involvement (P<0.01) and earlier stage disease (P<0.01). The overall 1-, 3- and 5-year survival rates for pancreatic body and tail cancer patients were 12.7% (25/197), 7.6% (15/197) and 2.5% (5/197), respectively, and ductal adenocarcinoma patients had worse survival rates [15.0% (9/60), 6.7% (4/60) and 1.7% (1/60), respectively] than cystadenocarcinoma patients [53.8% (21/39), 28.2% (11/39) and 10.3% (4/39)] (P<0.01). Moreover, the 1-, 3- and 5-year overall survival rates in patients with R0 resection were 55.3% (26/47), 31.9% (15/47) and 10.6% (5/47), respectively, significantly better than those in patients with palliative resection [9.5% (2/21), 0 and 0] and in patients with bypass or laparotomy [1.2% (1/81), 0 and 0] (P<0.01). Early diagnosis is crucial for increasing the radical resection rate, and radical resection plays an important role in improving survival for pancreatic body and tail cancer patients.

Expression of Nerve Growth Factor in Human Pancreatic β Cells

Nerve growth factor (NGF) is an important modulator of rat pancreatic β-cell physiology in vitro. In this study, we analysed the expression of NGF, TrkA and insulin in human pancreatic islets from normal, ductal adenocarcinoma and insulinoma-afflicted samples, using double immunofluorescent labelling and confocal microscopy.We found that in normal human pancreas, insulin and NGF are co-expressed in β cells. Moreover, similar to previous observations in rat, the high affinity NGF receptor TrkA is also expressed in β cells.Pancreatic β cells in normal islets from adenocarcinoma and mucinous cystadenocarcinoma patients also expressed NGF. In 2 out of 15 exocrine tumour samples, NGF was detected also in the tissue surrounding the islets, while 2 out of 13 adenocarcinoma tumours expressed this growth factor.In five insulinoma samples, we observed weaker immunofluorescent labelling of insulin and NGF in the neoplastic tissue, compared to the islets not afflicted by the tumour, which may be a consequence of increased hormone secretion rate.We demonstrate that human β cells express TrkA and NGF. These findings are consistent with the hypothesis that NGF modulates insulin secretion through a paracrine/autocrine loop, similar to the one observed in cultured rat β cells.

Hepatobiliary Cystadenoma and Cystadenocarcinoma

Fifty-two hepatobiliary cystadenomas and 18 hepatobiliary cystadenocarcinomas were drawn from the files of the Armed Forces Institute of Pathology and Rhode Island Hospital and studied in an attempt to correlate light microscopic features of the tumors with immunohistochemical and follow-up data. The cystadenoma patients ranged in age from 2 to 87 years at the time of initial diagnosis (mean, 45 years). All the cystadenomas were multilocular with benign cuboidal to columnar epithelium, and 44 (85%) had densely cellular spindle cell ("ovarian-like") stromata; 96% were female. Fifty-one cystadenomas were macrocystic lesions, typically lined by mucinous epithelium; one of the benign lesions was a serous cystadenoma (microcystic adenoma) reminiscent of the more commonly encountered pancreatic lesion of the same name. The cystadenocarcinoma patients ranged in age from 24 to 90 years at the time of first diagnosis (mean, 59 years); eight patients (44%) were male. All but one of the lesions were multilocular with malignant in situ (one case) or invasive tubulopapillary (15 cases), solid (one case), or adenosquamous (one case) epithelial components. Areas of preexisting benign cystadenoma were found in six (33%), an observation suggesting that benign lesions may evolve into malignant ones in some patients. Most cystadenomas and cystadenocarcinomas arose in the liver, a few in the extrahepatic biliary system (including the gallbladder). On follow-up, the cystadenoma patients in general were successfully treated by surgical excision of the lesions in toto; patients treated by subtotal resection often had persistent symptomatic disease. Four cystadenocarcinoma patients died of their tumors; another two patients were alive with persistent disease at last follow-up. In both the benign and the malignant lesions, most tumor cells were positive on immunohistochemical staining with antibodies to cytokeratin, epithelial membrane antigen, and carcinoembryonic antigen; scattered chromogranin-positive cells also appeared in a few tumors of both types. Immunohistochemistry did not yield a diagnostic immunoprofile to distinguish cystadenoma from cystadenocarcinoma or from other epithelial lesions arising within the abdominal cavity. At least two types of cystadenocarcinoma exist, one developing exclusively in female patients, usually accompanied by an "ovarian-like" stroma, which follows an indolent course; and the other, lacking the distinctive cellular stroma, seen in males, follows a more aggressive course and is more likely to result in the patient's death from tumor. It remains an open question whether the cystadenocarcinomas lacking a mesenchymal stroma, which arise in women, will follow the same aggressive course as similar lesions arising in men.