title: A Molecular Clock Infers Heterogeneous Tissue Age Among Patients with Barrett's Esophagus.
abstract: Biomarkers that drift differentially with age between normal and premalignant tissues, such as Barrett's esophagus (BE), have the potential to improve the assessment of a patient's cancer risk by providing quantitative information about how long a patient has lived with the precursor (i.e., dwell time). In the case of BE, which is a metaplastic precursor to esophageal adenocarcinoma (EAC), such biomarkers would be particularly useful because EAC risk may change with BE dwell time and it is generally not known how long a patient has lived with BE when a patient is first diagnosed with this condition. In this study we first describe a statistical analysis of DNA methylation data (both cross-sectional and longitudinal) derived from tissue samples from 50 BE patients to identify and validate a set of 67 CpG dinucleotides in 51 CpG islands that undergo age-related methylomic drift. Next, we describe how this information can be used to estimate a patient's BE dwell time. We introduce a Bayesian model that incorporates longitudinal methylomic drift rates, patient age, and methylation data from individually paired BE and normal squamous tissue samples to estimate patient-specific BE onset times. Our application of the model to 30 sporadic BE patients' methylomic profiles first exposes a wide heterogeneity in patient-specific BE onset times. Furthermore, independent application of this method to a cohort of 22 familial BE (FBE) patients reveals significantly earlier mean BE onset times. Our analysis supports the conjecture that differential methylomic drift occurs in BE (relative to normal squamous tissue) and hence allows quantitative estimation of the time that a BE patient has lived with BE.
authors.affiliation: Division of Gastroenterology, University of Washington School of Medicine, Seattle, Washington, United States of America.|Program in Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Kit
authors.identifier: 0000-0002-2678-0960
authors.initials: K
authors.lastname: Curtius
authors.affiliation: Program in Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Chao-Jen
authors.initials: CJ
authors.lastname: Wong
authors.affiliation: Program in Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: William D
authors.initials: WD
authors.lastname: Hazelton
authors.affiliation: Division of Gastroenterology, University of Washington School of Medicine, Seattle, Washington, United States of America.|Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Gastroenterology Section, VA Puget Sound Health Care System, Seattle, Washington, United States of America.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Kaz
authors.affiliation: University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Amitabh
authors.identifier: 0000-0002-0021-7862
authors.initials: A
authors.lastname: Chak
authors.affiliation: University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Willis
authors.affiliation: Division of Gastroenterology, University of Washington School of Medicine, Seattle, Washington, United States of America.|Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: William M
authors.initials: WM
authors.lastname: Grady
authors.affiliation: Program in Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: E Georg
authors.initials: EG
authors.lastname: Luebeck
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics; D001471:Barrett Esophagus / Q000209:etiology / Q000235:genetics*; D001499:Bayes Theorem; D001683:Biological Clocks / Q000235:genetics; D019295:Computational Biology; D018899:CpG Islands; D019175:DNA Methylation; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000209:etiology / Q000235:genetics; D005260:Female; D005819:Genetic Markers; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D012307:Risk Factors
chemical_list: D005819:Genetic Markers