Dataset Information

Gene Expression Signature-Based Prediction of Lymph Node Metastasis in Patients With Endometrioid Endometrial Cancer.

ABSTRACT: OBJECTIVE:This study aimed to develop a prediction model for lymph node metastasis using a gene expression signature in patients with endometrioid-type endometrial cancer. METHODS:Newly diagnosed endometrioid-type endometrial cancer cases in which the patients had undergone lymphadenectomy during a surgical staging procedure were identified from a national dataset (N = 330). Clinical and pathologic data were extracted from patient medical records, and gene expression datasets of their tumors were used to create a 12-gene predictive model for lymph node metastasis. We used principal components analysis on a training set (n = 110) to develop multivariate logistic models to predict low-risk patients having a probability of lymph node metastasis of less than 4%. The model with the highest prediction performance was selected for an evaluation set (n = 112), which, in turn, was validated in an independent validation set (n = 108). RESULTS:The model applied to the evaluation set showed 100% sensitivity (90% confidence interval [CI], 74%-100%) and 42% specificity (90% CI, 34%-51%), which resulted in 100% negative predictive value (90% CI, 89%-100%). In the validation set, we confirmed that the model consistently showed 100% sensitivity (90% CI, 88%-100%), 42% specificity (90% CI, 32%-50%), and 100% negative predictive value (90% CI, 88%-100%). CONCLUSIONS:Our 12-gene signature model is a useful tool for the identification of patients with endometrioid-type endometrial cancer at low risk of lymph node metastasis, particularly given that it can be used to analyze histologic tissue before surgery and used to tailor surgical options.

SUBMITTER: Kang S

PROVIDER: S-EPMC5780243 | biostudies-other | 2018 Feb

REPOSITORIES: biostudies-other

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Gene Expression Signature-Based Prediction of Lymph Node Metastasis in Patients With Endometrioid Endometrial Cancer.

Kang Sokbom S Thompson Zachary Z McClung E Claire EC Abdallah Reem R Lee Jae K JK Gonzalez-Bosquet Jesus J Wenham Robert M RM Chon Hye Sook HS

International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 20180201 2

<h4>Objective</h4>This study aimed to develop a prediction model for lymph node metastasis using a gene expression signature in patients with endometrioid-type endometrial cancer.<h4>Methods</h4>Newly diagnosed endometrioid-type endometrial cancer cases in which the patients had undergone lymphadenectomy during a surgical staging procedure were identified from a national dataset (N = 330). Clinical and pathologic data were extracted from patient medical records, and gene expression datasets of t ...[more]

PMID: 29194195

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Project description:BackgroundLymph node metastasis (LNM) is an important prognostic factor in endometrial cancer. Anomalous microRNAs (miRNAs) are associated with cell functions and are becoming a powerful tool to characterize malignant transformation and metastasis. The aim of this study was to construct a miRNA signature to predict LNM in endometrial endometrioid carcinoma (EEC).MethodCandidate target miRNAs related to LNM in EEC were screened by three methods including differentially expressed miRNAs (DEmiRs), weighted gene co-expression network analysis (WGCNA), and decision tree algorithms. Samples were randomly divided into the training and validation cohorts. A miRNA signature was built using a logistic regression model and was evaluated by the area under the curve (AUC) of receiver operating characteristic curve (ROC) and decision curve analysis (DCA). We also conducted pathway enrichment analysis and miRNA-gene regulatory network to look for potential genes and pathways engaged in LNM progression. Survival analysis was performed, and the miRNAs were tested whether they expressed differently in another independent GEO database.ResultThirty-one candidate miRNAs were screened and a final 15-miRNA signature was constructed by logistic regression. The model showed good calibration in the training and validation cohorts, with AUC of 0.824 (95% CI, 0.739-0.912) and 0.821 (95% CI, 0.691-0.925), respectively. The DCA demonstrated the miRNA signature was clinically useful. Hub miRNAs in signature seemed to contribute to EEC progression via mitotic cell cycle, cellular protein modification process, and molecular function. MiR-34c was statistically significant in survival that a higher expression of miR-34c indicated a higher survival time. MiR-34c-3p, miR-34c-5p, and miR-34b-5p were expressed differentially in GSE75968.ConclusionThe miRNA signature could work as a noninvasive method to detect LNM in EEC with a high prediction accuracy. In addition, miR-34c cluster may be a key biomarker referring LNM in endometrial cancer.

Project description:BackgroundLymph node metastasis (LNM) is a critical unfavorable prognostic factor in endometrial cancer (EC). At present, models involving molecular indicators that accurately predict LNM are still uncommon. We addressed this gap by developing nomograms to individualize the risk of LNM in EC and to identify a low-risk group for LNM.MethodsIn all, 776 patients who underwent comprehensive surgical staging with pelvic lymphadenectomy at the First Affiliated Hospital of Chongqing Medical University were divided into a training cohort (used for building the model) and a validation cohort (used for validating the model) according to a predefined ratio of 7:3. Logistics regression analysis was used in the training cohort to screen out predictors related to LNM, after which a nomogram was developed to predict LNM in patients with EC. A calibration curve and consistency index (C-index) were used to estimate the performance of the model. A receiver operating characteristic (ROC) curve and Youden index were used to determine the optimal threshold of the risk probability of LNM predicted by the model proposed in this study. Then, the prediction performance of different models and their discrimination abilities for identifying low-risk patients were compared.ResultLNM occurred in 87 and 42 patients in the training and validation cohorts, respectively. Multivariate logistic regression analysis showed that histological grade (P=0.022), myometrial invasion (P=0.002), lymphovascular space invasion (LVSI) (P=0.001), serum CA125 (P=0.008), Ki67 (P=0.012), estrogen receptor (ER) (0.009), and P53 (P=0.003) were associated with LNM; a nomogram was then successfully established on this basis. The internal and external calibration curves showed that the model fits well, and the C-index showed that the prediction accuracy of the model proposed in this study was better than that of the other models (the C-index of the training and validation cohorts was 0.90 and 0.91, respectively). The optimal threshold of the risk probability of LNM predicted by the model was 0.18. Based on this threshold, the model showed good discrimination for identifying low-risk patients.ConclusionCombining molecular indicators based on classical clinical parameters can predict LNM of patients with EC more accurately. The nomogram proposed in this study showed good discrimination for identifying low-risk patients with LNM.

Project description:Objective: To compare the prognostic predictive performance of six lymph node (LN) staging schemes: American Joint Committee on Cancer (AJCC) N stage, number of retrieved lymph nodes (NRLN), number of positive lymph nodes (NPLN), number of negative lymph nodes (NNLN), lymph node ratio (LNR), and log odds of positive lymph nodes (LODDS) among node-positive endometrioid endometrial cancer (EEC) patients. Methods: A total of 3,533 patients diagnosed with node-positive EEC between 2010 and 2016 from the Surveillance, Epidemiology, and End Results (SEER) database were retrospectively analyzed. We applied X-tile software to identify the optimal cutoff value for different staging schemes. Univariate and multivariate Cox regression models were used to assess the relationships between different LN schemes and survival outcomes [disease-specific survival (DSS) and overall survival (OS)]. Moreover, Akaike information criterion (AIC) and Harrell concordance index (C-index) were used to evaluate the predictive performance of each scheme in both continuous and categorical patterns. Results: N stage (N1/N2) was not an independent prognostic factor for node-positive EEC patients based on multivariate analysis (DSS: p = 0.235; OS: p = 0.145). Multivariate model incorporating LNR demonstrated the most superior goodness of fit regardless of continuous or categorical pattern. Regarding discrimination power of the models, LNR outperformed other models in categorical pattern (OS: C-index = 0.735; DSS: C-index = 0.737); however, LODDS obtained the highest C-index in continuous pattern (OS: 0.736; DSS: 0.739). Conclusions: N stage (N1/N2) was unable to differentiate the prognosis for node-positive EEC patients in our study. However, LNR and LODDS schemes seemed to have a better predictive performance for these patients than other number-based LN schemes whether in DSS or OS, which revealed that LNR and LODDS should be more helpful in prognosis assessment for node-positive EEC patients than AJCC N stage.

Project description:BackgroundEndometrial cancer (EC) with metastasis in pelvic/para-aortic lymph nodes suggests an unsatisfactory prognosis. Nevertheless, there is still rare literature focusing on the role of epithelial-mesenchymal transition (EMT) in lymph node metastasis (LNM) in EC.MethodsTranscriptional data were derived from the TCGA database. Patients with stage IA-IIIC2 EC were included, constituting the LN-positive and LN-negative groups. To evaluate the extent of EMT, an EMT signature composed of 315 genes was adopted. The EMT-related genes (ERGs) were obtained from the dbEMT2 database, and the differentially expressed ERGs (DEERGs) between these two groups were screened. On the basis of DEERGs, pathway analysis was carried out. We eventually adopted the logistic regression model to build an ERG-based gene signature with predictive value for LNM in EC.ResultsA total of 498 patients were included, with 75 in the LN-positive group. Median EMT score of tumor tissues from LN-negative group was - 0.369, while that from the LN-positive group was - 0.296 (P < 0.001), which clearly exhibited a more mesenchymal phenotype for LNM cases on the EMT continuum. By comparing expression profiles, 266 genes were identified as DEERGs, in which 184 were upregulated and 82 were downregulated. In pathway analysis, various EMT-related pathways were enriched. DEERGs shared between molecular subtypes were comparatively few. The ROC curve and logistic regression analysis screened 7 genes with the best performance to distinguish between the LN-positive and LN-negative group, i.e., CIRBP, DDR1, F2RL2, HOXA10, PPARGC1A, SEMA3E, and TGFB1. A logistic regression model including the 7-gene-based risk score, age, grade, myometrial invasion, and histological subtype was built, with an AUC of 0.850 and a favorite calibration (P = 0.074). In the validation dataset composed of 83 EC patients, the model exhibited a satisfactory predictive value and was well-calibrated (P = 0.42).ConclusionThe EMT status and expression of ERGs varied in LNM and non-LNM EC tissues, involving multiple EMT-related signaling pathways. Aside from that, the distribution of DEERGs differed among molecular subtypes. An ERG-based gene signature including 7 DEERGs exhibited a desirable predictive value for LNM in EC, which required further validation based upon clinical specimens in the future.

Project description:BackgroundThe current study aimed to develop a deep learning (DL) model for prediction of lymph node metastasis (LNM) based on hematoxylin and eosin (HE)-stained histopathological images of endometrial cancer (EC). The model was validated using external data.MethodsA total of 2,104 whole slide image (WSI) from 564 patients with pathologically confirmed LNM status were collated from West China Second University Hospital. An artificial intelligence (AI) model was built on the multiple instance-learning (MIL) framework for automatic prediction of the probability of LNM and its performance compared with "Mayo criteria". An additional external data source comprising 533 WSI was collected from two independent medical institutions to validate the model's robustness. Heatmaps were generated to demonstrate regions of the WSI that made the greatest contributions to the DL network output to improve understanding of these processes.ResultsThe proposed MIL model achieved an area under the curve (AUC) of 0.938, a sensitivity of 0.830 and a specificity of 0.911 for LNM prediction to EC. The AUC according to Mayo criteria was 0.666 for the same test dataset. For types I, II and mixed EC, AUCs were 0.927, 0.979 and 0.929, respectively. The predictive performance of the MIL model also achieved an AUC of 0.921 for early staging. In external validation data, the proposed model achieved an AUC of 0.770, a sensitivity of 0.814 and a specificity of 0.520 for LNM prediction. AUCs were 0.783 for type I and 0.818 for early stage EC.ConclusionsThe proposed MIL model generated from histopathological images of EC has a much better LNM predictive performance than that of Mayo criteria. A novel DL-based biomarker trained on different histological subtypes of EC slides was revealed to predict metastatic status with improved accuracy, especially for early staging patients. The current study proves the concept of MIL-based prediction of LNM in EC for the first time, and brought a new sight to improve the accuracy of LNM prediction. Multicenter prospective validation data is required to further confirm the clinical utility.

Dataset Information

Gene Expression Signature-Based Prediction of Lymph Node Metastasis in Patients With Endometrioid Endometrial Cancer.

Publications

Gene Expression Signature-Based Prediction of Lymph Node Metastasis in Patients With Endometrioid Endometrial Cancer.

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