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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA091955-11A1
Application #
8668335
Study Section
Special Emphasis Panel (ZCA1-RPRB-B (J1))
Project Start
2002-08-16
Project End
2019-03-31
Budget Start
2014-09-18
Budget End
2015-03-31
Support Year
11
Fiscal Year
2014
Total Cost
$167,129
Indirect Cost
$4,211
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Cheng, Yichen; Dai, James Y; Paulson, Thomas G et al. (2017) Quantification of Multiple Tumor Clones Using Gene Array and Sequencing Data. Ann Appl Stat 11:967-991
Reid, Brian J (2017) Genomics, Endoscopy, and Control of Gastroesophageal Cancers: A Perspective. Cell Mol Gastroenterol Hepatol 3:359-366
Andor, Noemi; Maley, Carlo C; Ji, Hanlee P (2017) Genomic Instability in Cancer: Teetering on the Limit of Tolerance. Cancer Res 77:2179-2185
Aktipis, Athena; Maley, Carlo C (2017) Cooperation and cheating as innovation: insights from cellular societies. Philos Trans R Soc Lond B Biol Sci 372:
Maley, Carlo C; Aktipis, Athena; Graham, Trevor A et al. (2017) Classifying the evolutionary and ecological features of neoplasms. Nat Rev Cancer 17:605-619
Lote, H; Spiteri, I; Ermini, L et al. (2017) Carbon dating cancer: defining the chronology of metastatic progression in colorectal cancer. Ann Oncol 28:1243-1249
Buas, Matthew F; Gu, Haiwei; Djukovic, Danijel et al. (2017) Candidate serum metabolite biomarkers for differentiating gastroesophageal reflux disease, Barrett's esophagus, and high-grade dysplasia/esophageal adenocarcinoma. Metabolomics 13:
Fortunato, Angelo; Boddy, Amy; Mallo, Diego et al. (2017) Natural Selection in Cancer Biology: From Molecular Snowflakes to Trait Hallmarks. Cold Spring Harb Perspect Med 7:
Tollis, Marc; Boddy, Amy M; Maley, Carlo C (2017) Peto's Paradox: how has evolution solved the problem of cancer prevention? BMC Biol 15:60
Chowell, Diego; Napier, James; Gupta, Rohan et al. (2017) Modeling the subclonal evolution of cancer cell populations. Cancer Res :

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