A multicenter, double-blinded validation study of methylation biomarkers for progression prediction in Barrett's esophagus.
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.
Jin
Zhe
Z
Gastroenterology Division, Johns Hopkins University, Baltimore, MD 21287, USA.
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
D000367:Age Factors; D001471:Barrett Esophagus / Q000473:pathology* / Q000503:physiopathology; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018450:Disease Progression; D004311:Double-Blind Method; D004724:Endoscopy; D004938:Esophageal Neoplasms / Q000453:epidemiology* / Q000473:pathology; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic; D012372:ROC Curve; D015203:Reproducibility of Results; D018570:Risk Assessment
D015415:Biomarkers; C000614131:CDKN2A protein, human; D050677:Core Binding Factor Alpha 3 Subunit; D019941:Cyclin-Dependent Kinase Inhibitor p16; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C493729:Runx3 protein, human; C423567:TMEFF2 protein, human