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Integrated Bioinformatics analysis and clinical validation reveals that high expression of mucin 1 in intrahepatic cholangiocarcinoma predicts recurrence after curative resection.

ABSTRACT: Intrahepatic cholangiocarcinoma (ICC) is a cancer type with high malignancy and a current lack of biomarkers to predict recurrence. In the present study, to identify potential biomarkers, five ICC datasets from the Gene Expression Omnibus database were analyzed to construct initial datasets by using a robust rank aggregation approach. A total of 19 upregulated genes were identified in the initial datasets. The genes identified were then further analysed using data from The Cancer Genome Atlas. Only mucin 1 (MUC1) exhibited significance regarding differential expression and survival prediction. Finally, the expression levels of MUC1 were assessed using reverse transcription-quantitative PCR in 61 pairs of ICC tumor and matched non-cancerous samples. The expression of MUC1 was significantly elevated in ICC tissues compared with that in matched non-cancerous counterparts (P=0.001). Patients with high MUC1 expression levels had significantly shorter overall survival (OS, P=0.009) and recurrence-free survival (RFS, P=0.012). MUC1 was identified as an independent prognostic factor for OS [hazard ratio (HR)=2.364, 95%CI: 1.214-4.485; P=0.023] and RFS (HR=2.552 95%CI: 1.294-5.032; P=0.007) in the multivariate analysis. Using receiver operating characteristic analysis, a co-index including MUC1 had a high accuracy for predicting survival [MUC1 combined with serum levels of CEA and cancer antigen 19-9, and lymph node metastasis, area under curve (AUC)=0.746, 95%CI: 0.620-0.872] and recurrence (MUC1 combined with bile duct invasion and lymph node metastasis, AUC=0.729, 95%CI: 0.605-854). In conclusion, MUC1 is highly expressed in ICC tissue and is a potential prognostic biomarker and therapeutic target for ICC.

SUBMITTER: Chen FY

PROVIDER: S-EPMC7480127 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Integrated Bioinformatics analysis and clinical validation reveals that high expression of mucin 1 in intrahepatic cholangiocarcinoma predicts recurrence after curative resection.

Chen Fei-Yu FY Zhou Cheng C Zhang Xiang-Yu XY Zhou Kai-Qian KQ Peng Yuan-Fei YF Yu Lei L Fan Jia J Zhou Jian J Hu Jie J Wang Zheng Z

Experimental and therapeutic medicine 20200903 5

Intrahepatic cholangiocarcinoma (ICC) is a cancer type with high malignancy and a current lack of biomarkers to predict recurrence. In the present study, to identify potential biomarkers, five ICC datasets from the Gene Expression Omnibus database were analyzed to construct initial datasets by using a robust rank aggregation approach. A total of 19 upregulated genes were identified in the initial datasets. The genes identified were then further analysed using data from The Cancer Genome Atlas. O ...[more]

PMID: 32952640

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Project description:Inflammation has a critical role in the development and progression of cancers. We developed a novel systemic inflammation score (SIS) based on lymphocyte, monocyte, and CA19-9 and explored its prognostic value in intrahepatic cholangiocarcinoma (ICC). From January 2005 to December 2011, 322 consecutive ICC patients who underwent curative resection in our center were included in this study, and validated in a retrospective study of 126 patients enrolled from 2012 to 2014. Clinicopathological variables including preoperative serum CA19-9 and LMR were analyzed. The cutoff values of CA19-9 and LMR were determined based on receiver operating characteristics curve analysis in the primary cohort. Kaplan-Meier curves and multivariate Cox-regression analyses were calculated for time to recurrence (TTR) and overall survival (OS). In univariate analysis of all patients, all three inflammatory and tumor marker including NLR ? 2.49 (P<0.001), LMR ? 4.45 (P=0.002), and CA19-9?89 (P<0.001) were associated with poor prognoses. When omitting SIS in multivariate analysis, preoperative LMR (P =0.006) and serum CA19-9 (P<0.001) were independent predictors of OS. In addition, elevated CA19-9 (P=0.001), multiple tumors (P<0.001), and lymph node metastasis (P<0.001) were significant predictors of worse recurrence free survival. Moreover, high SIS was significantly associated with aggressive tumor behaviours including large tumor size (P<0.001), multiple tumors (P=0.033), lymphonodus node metastasis (P=0.001), and high TNM stage (P<0.0001). Finally, univariate and multivariate analyses revealed the SIS was an independent predictor for TTR (HR=2.077, 95% CI, 1.365-3.162, P=0.001) and OS (HR=3.133 95% CI, 2.058-4.769, P<0.001). These results were further confirmed in the validation cohort. In conclusions, our findings demonstrate that the SIS as a potentially powerful prognostic biomarker in ICC that predicts poor clinical outcomes and is a promising tool for ICC treatment strategy decisions.

Project description:Early relapse after hepatectomy for intrahepatic cholangiocarcinoma (ICC) has a tremendous influence on the long-term survival outcomes of ICC patients. The purpose of our study was to investigate risk factors for early tumor relapse and confirm whether early relapse was correlated with ICC patients' long-term survival outcomes. Three hundred and twenty-two consecutive ICC patients undergoing partial hepatectomy at Liver Surgery Department of Zhongshan Hospital (Fudan University, Shanghai, China) between January 2005 and December 2011 were included in this retrospectively study. The definition of early relapse had been described as tumor relapse within 24 months after hepatectomy in ICC patients. We identified a total of 168 ICC patients with early relapse and 23 ICC patients with late relapse after hepatectomy. From the time of relapse, the long-term survival outcomes were worse among patients who had early vs. late relapse (median OS 16.5 vs. 44.7 months, respectively; P < 0.0001). The overall survival of the early relapse group was lower than that of the late relapse group (P < 0.0001). Multivariate Cox regression analysis indicated that multiple tumors (hazard ratio [HR], 1.951; 95% CI, 1.382-2.755; P < 0.001), lymphonodus metastasis (HR, 1.517; 95% CI, 1.061-2.168; P = 0.022), and higher serum CA19-9 levels (HR, 1.495; 95% CI, 1.095-2.039; P = 0.011) were independent risk factors of early relapse. Moreover, multiple tumors (HR, 1.641; 95% CI, 1.120-2.406; P = 0.011), lymphonodus metastasis (HR, 2.008; 95% CI, 1.367-2.949; P < 0.001), elevated NLR (HR, 1.921; 95% CI, 1.331-2.774; P < 0.001) and higher serum CA19-9 levels (HR, 1.990; 95% CI, 1.409-2.812; P < 0.001) were independent predictors of overall survival for ICC patients with early relapse. Collectively, our findings demonstrated that multiple tumors, lymphonodus metastasis, and higher serum CA19-9 levels were associated with the increased risks of early relapse and worse prognoses of ICC after curative-intent resection.

Project description:ImportanceAlthough surgery offers the best chance of a potential cure for patients with localized, resectable intrahepatic cholangiocarcinoma (ICC), prognosis of patients remains dismal largely because of a high incidence of recurrence.ObjectiveTo predict very early recurrence (VER) (ie, recurrence within 6 months after surgery) following resection for ICC in the pre- and postoperative setting.Design, setting, and participantsPatients who underwent curative-intent resection for ICC between May 1990 and July 2016 were identified from an international multi-institutional database. The study was conducted at The Ohio State University in collaboration with all other participating institutions. The data were analyzed in December 2019.Main outcomes and measuresTwo logistic regression models were constructed to predict VER based on pre- and postoperative variables. The final models were used to develop an online calculator to predict VER and the tool was internally and externally validated.ResultsAmong 880 patients (median age, 59 years [interquartile range, 51-68 years]; 388 women [44.1%]; 428 [50.2%] white; 377 [44.3%] Asian; 27 [3.2%] black]), 196 (22.3%) developed VER. The 5-year overall survival among patients with and without VER was 8.9% vs 49.8%, respectively (P < .001). A preoperative model was able to stratify patients relative to the risk for VER: low risk (6-month recurrence-free survival [RFS], 87.7%), intermediate risk (6-month RFS, 72.3%), and high risk (6-month RFS, 49.5%) (log-rank P < .001). The postoperative model similarly identified discrete cohorts of patients based on probability for VER: low risk (6-month RFS, 90.0%), intermediate risk (6-month RFS, 73.1%), and high risk (6-month RFS, 48.5%) (log-rank, P < .001). The calibration and predictive accuracy of the pre- and postoperative models were good in the training (C index: preoperative, 0.710; postoperative, 0.722) as well as the internal (C index: preoperative, 0.715; postoperative, 0.728; bootstrapping resamples, n = 5000) and external (C index: postoperative, 0.672) validation data sets.Conclusion and relevanceAn easy-to-use online calculator was developed to help clinicians predict the chance of VER after curative-intent resection for ICC. The tool performed well on internal and external validation. This tool may help clinicians in the preoperative selection of patients for neoadjuvant therapy as well as during the postoperative period to inform surveillance strategies.

Dataset Information

Integrated Bioinformatics analysis and clinical validation reveals that high expression of mucin 1 in intrahepatic cholangiocarcinoma predicts recurrence after curative resection.

Publications

Integrated Bioinformatics analysis and clinical validation reveals that high expression of mucin 1 in intrahepatic cholangiocarcinoma predicts recurrence after curative resection.

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