Project 3: Phylogenetic Analysis of Progression in Barrett's Esophagus It is generally accepted that cancer develops through a process of neoplastic evolution over time and space in the body, yet studying these evolutionary processes has proven nearly impossible, since tissue that is at risk for developing into cancer is almost always removed. We propose to characterize these evolutionary processes in Barrett's esophagus, a precursor to esophageal adenocarcinoma, which develops in the esophagus as an adaptation to chronic reflux. This premalignant tissue is not removed from the body when detected;instead, patients are enrolled in surveillance programs, allowing biopsies to be collected and genomic changes that evolve over time and space in vivo to be studied. We hypothesize that the initial expansion of Barrett's epithelium persists for a lifetime in most individuals with Barrett's and is associated with a low risk of progression to cancer. In a small percentage of Barrett's patients, a secondary expansion of cell populations with greatly increased genomic alterations spreads across in the already established Barrett's segment, and in this secondary expansion cancer develops. We propose to use phylogenetic analysis, a method adapted from evolutionary biology, to characterize the processes that determine the evolutionary pathway (stable, benign disease or progression to esophageal adenocarcinoma) that occurs in an individual. This will be accomplished using somatic genomic alteration data from high density SNP arrays and from whole genome sequencing of samples taken at multiple time points from a cohort of 248 patients, 79 of whom progressed to cancer during followup. Phylogenies can distinguish between gradual versus punctuated dynamics in the accumulation of genomic alterations. Phylogenies also allow inference ofthe genomic makeup of ancestral cell populations, providing novel targets for early detection and prevention strategies. These analyses will address a critical question that has been almost impossible to study: what are the processes that govern the evolution of cancer in vivo.

Public Health Relevance

Our study will allow us to characterize the genetic changes that occur in cancer cells from very eariy on in the process of cancer development. It has been neariy impossible to study how cancer cells change and evolve over time in actual patients. What we learn from this study will help identify when and what kind of treatments are most likely to help prevent the development of cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-RPRB-B (J1))
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Fred Hutchinson Cancer Research Center
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Dong, Jing; Levine, David M; Buas, Matthew F et al. (2018) Interactions Between Genetic Variants and Environmental Factors Affect Risk of Esophageal Adenocarcinoma and Barrett's Esophagus. Clin Gastroenterol Hepatol 16:1598-1606.e4
Xia, Li Charlie; Ai, Dongmei; Lee, Hojoon et al. (2018) SVEngine: an efficient and versatile simulator of genome structural variations with features of cancer clonal evolution. Gigascience 7:
Galipeau, Patricia C; Oman, Kenji M; Paulson, Thomas G et al. (2018) NSAID use and somatic exomic mutations in Barrett's esophagus. Genome Med 10:17
Martinez, Pierre; Mallo, Diego; Paulson, Thomas G et al. (2018) Evolution of Barrett's esophagus through space and time at single-crypt and whole-biopsy levels. Nat Commun 9:794
Dong, Jing; Buas, Matthew F; Gharahkhani, Puya et al. (2018) Determining Risk of Barrett's Esophagus and Esophageal Adenocarcinoma Based on Epidemiologic Factors and Genetic Variants. Gastroenterology 154:1273-1281.e3
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Reid, Brian J (2017) Genomics, Endoscopy, and Control of Gastroesophageal Cancers: A Perspective. Cell Mol Gastroenterol Hepatol 3:359-366

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