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A multicenter, double-blinded validation study of methylation biomarkers for progression prediction in Barrett's esophagus.

ABSTRACT: Esophageal adenocarcinoma risk in Barrett's esophagus (BE) is increased 30- to 125-fold versus the general population. Among all BE patients, however, neoplastic progression occurs only once per 200 patient-years. Molecular biomarkers are therefore needed to risk-stratify patients for more efficient surveillance endoscopy and to improve the early detection of progression. We therefore performed a retrospective, multicenter, double-blinded validation study of eight BE progression prediction methylation biomarkers. Progression or nonprogression were determined at 2 years (tier 1) and 4 years (tier 2). Methylation was assayed in 145 nonprogressors and 50 progressors using real-time quantitative methylation-specific PCR. Progressors were significantly older than nonprogressors (70.6 versus 62.5 years; P < 0.001). We evaluated a linear combination of the eight markers, using coefficients from a multivariate logistic regression analysis. Areas under the ROC curve (AUC) were high in the 2-year, 4-year, and combined data models (0.843, 0.829, and 0.840; P < 0.001, <0.001, and <0.001, respectively). In addition, even after rigorous overfitting correction, the incremental AUCs contributed by panels based on the 8 markers plus age versus age alone were substantial (Delta-AUC = 0.152, 0.114, and 0.118, respectively) in all 3 models. A methylation biomarker-based panel to predict neoplastic progression in BE has potential clinical value in improving both the efficiency of surveillance endoscopy and the early detection of neoplasia.

SUBMITTER: Jin Z

PROVIDER: S-EPMC2752375 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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A multicenter, double-blinded validation study of methylation biomarkers for progression prediction in Barrett's esophagus.

Jin Zhe Z Cheng Yulan Y Gu Wen W Zheng Yingye Y Sato Fumiaki F Mori Yuriko Y Olaru Alexandru V AV Paun Bogdan C BC Yang Jian J Kan Takatsugu T Ito Tetsuo T Hamilton James P JP Selaru Florin M FM Agarwal Rachana R David Stefan S Abraham John M JM Wolfsen Herbert C HC Wallace Michael B MB Shaheen Nicholas J NJ Washington Kay K Wang Jean J Canto Marcia Irene MI Bhattacharyya Achyut A Nelson Mark A MA Wagner Paul D PD Romero Yvonne Y Wang Kenneth K KK Feng Ziding Z Sampliner Richard E RE Meltzer Stephen J SJ

Cancer research 20090512 10

Esophageal adenocarcinoma risk in Barrett's esophagus (BE) is increased 30- to 125-fold versus the general population. Among all BE patients, however, neoplastic progression occurs only once per 200 patient-years. Molecular biomarkers are therefore needed to risk-stratify patients for more efficient surveillance endoscopy and to improve the early detection of progression. We therefore performed a retrospective, multicenter, double-blinded validation study of eight BE progression prediction methy ...[more]

PMID: 19435894

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Project description:Background & aimsPrediction of progression risk in Barrett's esophagus (BE) may enable personalized management. We aimed to assess the adjunct value of a tissue systems pathology test (TissueCypher) performed on paraffin-embedded biopsy tissue, when added to expert pathology review in predicting incident progression, pooling individual patient-level data from multiple international studies METHODS: Demographics, clinical features, the TissueCypher risk class/score, and progression status were analyzed. Conditional logistical regression analysis was used to develop multivariable models predicting incident progression with and without the TissueCypher risk class (low, intermediate, high). Concordance (c-) statistics were calculated and compared with likelihood ratio tests to assess predictive ability of models. A risk prediction calculator integrating clinical variables and TissueCypher risk class was also developed.ResultsData from 552 patients with baseline no (n = 472), indefinite (n = 32), or low-grade dysplasia (n = 48) (comprising 152 incident progressors and 400 non-progressors) were analyzed. A high-risk test class independently predicted increased risk of progression to high-grade dysplasia/adenocarcinoma (odds ratio, 6.0; 95% confidence interval, 2.9-12.0), along with expert confirmed low-grade dysplasia (odds ratio, 2.9; 95% confidence interval, 1.2-7.2). Model prediction of progression with the TissueCypher risk class incorporated was significantly superior than without, in the whole cohort (c-statistic 0.75 vs 0.68; P < .0001) and the nondysplastic BE subset (c-statistic 0.72 vs 0.63; P < .0001). Sensitivity and specificity of the high risk TissueCypher class were 38% and 94%, respectively.ConclusionsAn objective tissue systems pathology test high-risk class is a strong independent predictor of incident progression in patients with BE, substantially improving progression risk prediction over clinical variables alone. Although test specificity was high, sensitivity was modest.

Dataset Information

A multicenter, double-blinded validation study of methylation biomarkers for progression prediction in Barrett's esophagus.

Publications

A multicenter, double-blinded validation study of methylation biomarkers for progression prediction in Barrett's esophagus.

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