Objectives/Specific Aims: The hypothesis of this proposal is that characterization of aberrantly methylated genes in esophageal cell lines and tissues will lead to a better understanding of the initiation and progression of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) and has the promise to lead to the discovery of novel early-detection and/or prognostic markers for BE and EAC.
The specific aims of this proposal are: 1) To identify novel methylated loci involved in the initiation and progression of BE through the use of microarrays, 2) To perform high-resolution methylation analysis of the CpG dinucleotides in candidate tumor suppressor genes, and 3) To identify and validate a panel of methylated genes that discriminates BE, BE with high-grade dysplasia, and EAC and predicts the progression from BE to EAC. Research Design: 1. cDNA expression and """"""""methylation"""""""" arrays will be used to identify novel methylated genes in a unique panel of esophageal cell lines. 2. The pattern of CpG dinucleotide methylation will be analyzed in cell lines and primary tissues using MALDI-TOF technology. 3. A panel of candidate biomarkers will be tested in primary esophageal tissues, including normal esophagus, BE, BE with dysplasia, and cancer to determine their ability to discriminate between these histological tissue types. Candidate Career Goals and Career Development Plan: The candidate's goal is to become an academic physician-scientist performing translational research in the early-detection of cancer. The candidate's plan includes seeking out broad, interdisciplinary mentorship and enrolling in courses in biostatistics, bioinformatics, and clinical trial design to become a more complete and effective translational scientist. Relevance to Public Health: EAC is the most rapidly increasing cancer in the U.S., and most individuals diagnosed with EAC will never benefit from endoscopic screening. For this reason, a panel of novel DNA biomarkers promises to improve early-detection of BE or cancer and improve the dismal survival rate in patients diagnosed with esophageal adenocarcinoma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
3K08DK080630-02S1
Application #
7806300
Study Section
Subcommittee G - Education (NCI)
Program Officer
Podskalny, Judith M,
Project Start
2007-08-01
Project End
2012-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
2
Fiscal Year
2009
Total Cost
$1,080
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Kaz, Andrew M; Grady, William M (2014) Epigenetic biomarkers in esophageal cancer. Cancer Lett 342:193-9
Kaz, Andrew M; Luo, Yanxin; Dzieciatkowski, Slavomir et al. (2012) Aberrantly methylated PKP1 in the progression of Barrett's esophagus to esophageal adenocarcinoma. Genes Chromosomes Cancer 51:384-93
Kaz, Andrew M; Wong, Chao-Jen; Luo, Yanxin et al. (2011) DNA methylation profiling in Barrett's esophagus and esophageal adenocarcinoma reveals unique methylation signatures and molecular subclasses. Epigenetics 6:1403-12