The incidence of esophageal adenocarcinoma (EA), a rapidly fatal disease, has increased faster than any other cancer in the US over the last three decades - over 500 percent. Gastroesophageal reflux and obesity have been found to be key modifiable risk factors for the development of EA and its main precursor, Barrett's esophagus (BE). However, while reflux appears to be crucial to the neoplastic process, only about 10 - 15 percent of individuals with long-standing reflux symptoms develop BE in their lifetimes;among those who do, most do not progress to EA. Similarly, the mechanisms by which obesity increases risk of EA are not known. Thus, there must be other cofactors modulating the reflux-related chronic inflammatory effects on the esophageal epithelium and the local and systemic consequences of being overweight, that largely determine risk. Many of these cofactors are likely to be genetically mediated, and while family, twin and candidate gene studies support this notion, no genes have been established yet as playing a causal role. Here, we propose a large-scale genome-wide association study which takes advantage of the extensive data collected by investigators in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) in 18 epidemiologic studies, representing the vast majority of the well-designed largely population-based studies of these diseases in the world. The overall goal of our research is to evaluate the influence of genetic susceptibility on risk of EA and BE. The primary aim is to identify tagSNPs most strongly associated with risk of BE and EA. In secondary aims we will evaluate the extent to which the most significant associations vary according to key environmental and host risk factors for these conditions, including gender, obesity and cigarette smoking. We propose a single phase approach over three years involving 7,500 participants, all of whom have been previously interviewed regarding major environmental and host risk factors and have donated blood specimens. The Illumina Infinium Human 610-Quad Chip will be used to genotype approximately 1,500 cases of EA, 3,000 cases of BE and 3,000 population controls. Additional sources of samples and data have been identified to provide replication studies (funding to be requested separately.) The resources of BEACON, together with recent advances in genomic technology and analytic methods, present a unique and cost-effective opportunity to a) study the influence of genetic and environmental factors in the etiology of these important diseases, b) aid in the identification of key biological pathways in their pathogenesis, and c) help target persons at highest risk so that screening, prevention and surveillance efforts can be directed most effectively.

Public Health Relevance

The incidence of esophageal adenocarcinoma, a rapidly fatal disease, has increased more than six-fold over the past 30 years. By conducting a large-scale genome-wide association study using pooled data and DNA from 18 epidemiologic studies, we propose to evaluate the influence of genetic susceptibility on risk of this cancer and its main precancerous condition, Barrett's esophagus, and determine the extent to which susceptibility factors vary according to key environmental and host risk factors for these conditions. These results will aid in the identification of biological pathways important in the etiology of this cancer, and help target persons at highest risk so that screening, prevention and surveillance efforts can be directed most effectively.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA136725-01A1
Application #
7730733
Study Section
Special Emphasis Panel (ZRG1-HOP-V (02))
Program Officer
Seminara, Daniela
Project Start
2009-09-21
Project End
2012-08-31
Budget Start
2009-09-21
Budget End
2010-08-31
Support Year
1
Fiscal Year
2009
Total Cost
$3,448,940
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
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
Bailey, Jessica N Cooke; Gharahkhani, Puya; Kang, Jae H et al. (2018) Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets. Invest Ophthalmol Vis Sci 59:629-636
Dai, James Y; Wang, Xiaoyu; Buas, Matthew F et al. (2018) Whole-genome sequencing of esophageal adenocarcinoma in Chinese patients reveals distinct mutational signatures and genomic alterations. Commun Biol 1:174
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
Buas, Matthew F; He, Qianchuan; Johnson, Lisa G et al. (2017) Germline variation in inflammation-related pathways and risk of Barrett's oesophagus and oesophageal adenocarcinoma. Gut 66:1739-1747
Contino, Gianmarco; Vaughan, Thomas L; Whiteman, David et al. (2017) The Evolving Genomic Landscape of Barrett's Esophagus and Esophageal Adenocarcinoma. Gastroenterology 153:657-673.e1
Gharahkhani, Puya; Tung, Joyce; Hinds, David et al. (2016) Chronic gastroesophageal reflux disease shares genetic background with esophageal adenocarcinoma and Barrett's esophagus. Hum Mol Genet 25:828-35
Ek, Weronica E; Lagergren, Katarina; Cook, Michael et al. (2016) Polymorphisms in genes in the androgen pathway and risk of Barrett's esophagus and esophageal adenocarcinoma. Int J Cancer 138:1146-52
Gharahkhani, Puya; Fitzgerald, Rebecca C; Vaughan, Thomas L et al. (2016) Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis. Lancet Oncol 17:1363-1373
Dai, James Y; Tapsoba, Jean de Dieu; Buas, Matthew F et al. (2016) Constrained Score Statistics Identify Genetic Variants Interacting with Multiple Risk Factors in Barrett's Esophagus. Am J Hum Genet 99:352-65

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