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.
Gastroenterology Division, Johns Hopkins University, Baltimore, MD 21287, USA.
Zhe
Z
Jin
Yulan
Y
Cheng
Wen
W
Gu
Yingye
Y
Zheng
Fumiaki
F
Sato
Yuriko
Y
Mori
Alexandru V
AV
Olaru
Bogdan C
BC
Paun
Jian
J
Yang
Takatsugu
T
Kan
Tetsuo
T
Ito
James P
JP
Hamilton
Florin M
FM
Selaru
Rachana
R
Agarwal
Stefan
S
David
John M
JM
Abraham
Herbert C
HC
Wolfsen
Michael B
MB
Wallace
Nicholas J
NJ
Shaheen
Kay
K
Washington
Jean
J
Wang
Marcia Irene
MI
Canto
Achyut
A
Bhattacharyya
Mark A
MA
Nelson
Paul D
PD
Wagner
Yvonne
Y
Romero
Kenneth K
KK
Wang
Ziding
Z
Feng
Richard E
RE
Sampliner
Stephen J
SJ
Meltzer
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