The vast majority of esophageal cancers will develop metastatic disease eventually. Our preliminary data suggest that certain genetic polymorphisms in key pathways may affect survival or prognosis in esophageal and other cancers. Currently, relatively uniform treatment regimens are applied to all patients. A better understanding of the association between germline polymorphisms and prognosis may lead to better treatment strategies and improved outcomes. The proposed study will expand an existing cohort of over 300 esophageal cancer patients established by the Pl's team from 1999-2003 and recruited originally for a pilot case-control study, with the goal of recruiting a total cohort of over 500 patients. Each patient will have a minimum of 3 years of follow-up (and up to 8 years) by the end of the proposed study period. Our overarching aim is to evaluate the roles of genetic polymorphisms in various pathways and their association with esophageal cancer outcomes. The proposed pathways include DNA repair (e.g. ERCC1 ), matrix metalloproteinases, and cell cycle dysregulation (e.g. p53). In addition, polymorphisms of genes involved in the xenobiotic metabolism of commonly-used chemotherapy agents will be assessed, including glutatione stransferases (metabolism of platinum agents), thymidylate synthase (5-fluorouracil), CYP3A5 (taxanes), and UGT1A1 (irinotecan). Outcomes of interest will include disease-free or progression-free survival, and overall survival. To evaluate polymorphisms in linkage disequilibrium, novel in silico haplotyping techniques will be applied. Where feasible, polymorphisms will be correlated with potential biomarkers, such as protein over-expression by immunohistochemical staining. The proposed studies will take advantage of a well-established and well-characterized cohort, an associated extensive pre-treatment tissue bank, and a comprehensive set of preliminary and feasibility results. Furthermore, the proposed studies address directly a prioritized research area identified by the NCI Stomach and Esophageal Cancers Progress Review Group (Year 2002).

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA109193-01
Application #
6813650
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Thurin, Magdalena
Project Start
2004-08-05
Project End
2009-07-31
Budget Start
2004-08-05
Budget End
2005-07-31
Support Year
1
Fiscal Year
2004
Total Cost
$444,604
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Cheung, Winson Y; Zhai, Rihong; Bradbury, Penny et al. (2012) Single nucleotide polymorphisms in the matrix metalloproteinase gene family and the frequency and duration of gastroesophageal reflux disease influence the risk of esophageal adenocarcinoma. Int J Cancer 131:2478-86
Zhai, Rihong; Zhao, Yang; Su, Li et al. (2012) Genome-wide DNA methylation profiling of cell-free serum DNA in esophageal adenocarcinoma and Barrett esophagus. Neoplasia 14:29-33
Wu, I-Chen; Zhao, Yang; Zhai, Rihong et al. (2011) Association between polymorphisms in cancer-related genes and early onset of esophageal adenocarcinoma. Neoplasia 13:386-92
Zhai, Rihong; Chen, Feng; Liu, Geoffrey et al. (2010) Interactions among genetic variants in apoptosis pathway genes, reflux symptoms, body mass index, and smoking indicate two distinct etiologic patterns of esophageal adenocarcinoma. J Clin Oncol 28:2445-51
Liu, Chen-Yu; Wu, Michael C; Chen, Feng et al. (2010) A Large-scale genetic association study of esophageal adenocarcinoma risk. Carcinogenesis 31:1259-63
Cheung, Winson Y; Zhai, Rihong; Kulke, Matthew H et al. (2009) Epidermal growth factor A61G gene polymorphism, gastroesophageal reflux disease and esophageal adenocarcinoma risk. Carcinogenesis 30:1363-7
Cheung, Winson Y; Liu, Geoffrey (2009) Genetic variations in esophageal cancer risk and prognosis. Gastroenterol Clin North Am 38:75-91, viii
Bradbury, Penelope A; Zhai, Rihong; Ma, Clement et al. (2009) Vascular endothelial growth factor polymorphisms and esophageal cancer prognosis. Clin Cancer Res 15:4680-5
Lanuti, Michael; Liu, Geoffrey; Goodwin, Jonathan M et al. (2008) A functional epidermal growth factor (EGF) polymorphism, EGF serum levels, and esophageal adenocarcinoma risk and outcome. Clin Cancer Res 14:3216-22

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