This application brings together an experienced team of investigators into a P01 to study Barrett's esophagus (BE), the only established precursor of esophageal adenocarcinoma (EA), a rapidly increasing, highly lethal malignancy. BE is also a unique in vivo model of human epithelial neoplasia, and the P01 theme of genomic instability: its etiology, manifestations and progression focuses on fundamental mechanisms of human neoplastic progression. Thus, our primary and secondary goals are to (1) reduce morbidity and mortality of EA by early detection, prevention, or both and (2) elucidate mechanisms of human neoplastic progression in vivo that may be shared by other neoplasms whose early stages are less amenable to investigation. Our study design is a prospective investigation of the Seattle Barrett's Esophagus Cohort, one of the largest and best characterized in the world. All data in the P01 will be derived from this cohort, maintained by Core B (Clinical Research). Project 1 (Clonal Evolution) hypothesizes that the evolution of clonal lesions in p16, p53 and ploidy are intrinsic to mechanisms of neoplastic progression. It seeks to determine the extent to which they predict neoplastic progression in BE and to identify transcription patterns that mediate transitions from one stage of progression to another and give rise to EA. Project 2 (Epidemiology) hypothesizes that environmental exposures and host factors, including NSAIDs, serum selenium, bile reflux, high fat, low fruit and vegetable diet and being overweight, modulate progression. It seeks to determine the extent to which these factors are associated with the genetic markers that are developed in Projects 1 and 3, as well as clinical outcome as assessed by Core B. Project 3 (Genetic Instability) hypothesizes that loss of normal mechanisms that insure genomic stability is an early event that contributes to neoplastic progression in BE. The mechanisms that contribute to chromosomal and mitotic instability will be studied, and the utility of measures of genetic instability as predictors of clinical prognosis and as targets for therapeutic intervention will be determined. The P01 is highly collaborative and all projects and cores interact with each other. Thus, the clonal markers and measures of instability provided by Projects 1 and 3, respectively, become shared resources to advance the common goals of the P01. These interactions are facilitated by Core C (Bioinformatics/Biostatistics), which provides a framework for analysis of the complicated datasets of the projects and a vehicle for interproject and core communications.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA091955-02
Application #
6647703
Study Section
Subcommittee G - Education (NCI)
Program Officer
Srivastava, Sudhir
Project Start
2002-08-16
Project End
2007-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
2
Fiscal Year
2003
Total Cost
$2,237,165
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Barry, Peter; Vatsiou, Alexandra; Spiteri, Inmaculada et al. (2018) The Spatiotemporal Evolution of Lymph Node Spread in Early Breast Cancer. Clin Cancer Res 24:4763-4770
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
Chowell, Diego; Napier, James; Gupta, Rohan et al. (2018) Modeling the Subclonal Evolution of Cancer Cell Populations. Cancer Res 78:830-839
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
Andor, Noemi; Maley, Carlo C; Ji, Hanlee P (2017) Genomic Instability in Cancer: Teetering on the Limit of Tolerance. Cancer Res 77:2179-2185
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:

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