Cancer is a disease of somatic genomic evolution;and all cancers are believed to arise as a result of somatic genomic instability, generation of mutations and evolution of neoplastic cell lineages that lead to cancer. The incidence and mortality of esophageal adenocarcinoma (EA) have been increasing more rapidly than any other cancer in the United States for the past four decades. Barrett's esophagus (BE) is the only known precursor to EA. However, current screening strategies selectively detect slowly or non-progressing BE that does not progress to EA over a lifetime ("over diagnosis"). In contrast, most EA arise in patients without a prior diagnosis of BE even though the evidence indicates that BE was present but undiagnosed ("under diagnosis"). Over- and under diagnosis are believed to due to length bias in which screening misses rapidly progressive BE while selectively detecting slowly progressive BE. However, almost nothing is known about the biology underlying length bias. During the current funding period, in a longitudinal case-cohort study, we made transformative advances in defining the biology underlying rapid and slowly or non-progressive BE. We found that rapidly progressive BE was characterized by chromosome instability and a four year window of opportunity for early detection of EA whereas BE that did not progress to EA largely maintained somatic genome stability over prolonged periods. We will build on these transformative advances. Our P01 is designed to impact all levels of care from population screening to specialized treatment of patients with BE. Project 1 will determine mutation frequencies at two time points that are associated with progression to EA to improve our understanding of somatic genome dynamics that govern progression and extend the window of opportunity for early detection of cancer. Project 3 will use phylogenetic methods, which look backwards in time, to infer the ancestral lineages of BE in individuals who do and do not progress to EA as well as in individuals pre- and post-endoscopic therapy. This will allow us to identify ancestral lineages that occur early during this evolutionary process that can be used for early detection of EA and improve outcomes of endoscopic therapy. Project 2 will build risk models (1) incorporating GWAS and SGA at two time points, (2) determining relationships among host and environmental factors, and constitutive and somatic genomic alterations pre- and post-endoscopic therapy to predict response to therapy, and (3) incorporate these findings into a comprehensive model to inform (1) screening, (2) surveillance, (3) prevention and (4) endoscopic therapy.

Public Health Relevance

Most individuals with BE never develop EA, but undergo routine cancer surveillance indefinitely. Successful completion of our research will have a profound impact on screening, surveillance, prevention and treatment strategies for BE/EA. It will also have a profound impact on our understanding of the rate of mutations that transforms a BE cell to a cancer cell, which will be applicable to most cancers, including breast, ovary, lung and colon, which are more difficult to study overtime in the same individual.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA091955-11A1
Application #
8668332
Study Section
Special Emphasis Panel (ZCA1-RPRB-B (J1))
Program Officer
Srivastava, Sudhir
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
$2,528,093
Indirect Cost
$1,005,697
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Li, Xiaohong; Blount, Patricia L; Reid, Brian J et al. (2014) Quantification of population benefit in evaluation of biomarkers: practical implications for disease detection and prevention. BMC Med Inform Decis Mak 14:15
Vaughan, Thomas L (2014) From genomics to diagnostics of esophageal adenocarcinoma. Nat Genet 46:806-7
Thrift, Aaron P; Shaheen, Nicholas J; Gammon, Marilie D et al. (2014) Obesity and risk of esophageal adenocarcinoma and Barrett's esophagus: a Mendelian randomization study. J Natl Cancer Inst 106:
Buas, Matthew F; Levine, David M; Makar, Karen W et al. (2014) Integrative post-genome-wide association analysis of CDKN2A and TP53 SNPs and risk of esophageal adenocarcinoma. Carcinogenesis 35:2740-7
Alcock, Joe; Maley, Carlo C; Aktipis, C Athena (2014) Is eating behavior manipulated by the gastrointestinal microbiota? Evolutionary pressures and potential mechanisms. Bioessays 36:940-9
Lu, Yi; Ek, Weronica E; Whiteman, David et al. (2014) Most common 'sporadic' cancers have a significant germline genetic component. Hum Mol Genet 23:6112-8
Li, Xiaohong; Galipeau, Patricia C; Paulson, Thomas G et al. (2014) Temporal and spatial evolution of somatic chromosomal alterations: a case-cohort study of Barrett's esophagus. Cancer Prev Res (Phila) 7:114-27
Hardikar, Sheetal; Onstad, Lynn; Song, Xiaoling et al. (2014) Inflammation and oxidative stress markers and esophageal adenocarcinoma incidence in a Barrett's esophagus cohort. Cancer Epidemiol Biomarkers Prev 23:2393-403
Hardikar, Sheetal; Song, Xiaoling; Kratz, Mario et al. (2014) Intraindividual variability over time in plasma biomarkers of inflammation and effects of long-term storage. Cancer Causes Control 25:969-76
Sprouffske, Kathleen; Athena Aktipis, C; Radich, Jerald P et al. (2013) An evolutionary explanation for the presence of cancer nonstem cells in neoplasms. Evol Appl 6:92-101

Showing the most recent 10 out of 76 publications