The development of colorectal cancer (CRC) is a multi-step process, called the polyp to cancer sequence, resulting from the accumulation of genomic alterations and epigenetic alterations in colon epithelial cells. These epigenetic alterations include the aberrant methylation of the 5'promoter region of genes with CpG islands, which can silence the expression of tumor suppressor genes. The accumulation of aberrantly methylated genes begins at the pre-cancer phase of CRC formation and is common in CRC, affecting thousands of genes, and resulting in a variety of different tumor promoting biological effects on the CRCs. An unanswered question is how the methylated genes vary between the known CRC molecular subgroups, Chromosomal Unstable (CIN), Microsatellite Unstable (MSI), and CpG Island Methylator Phenotype (CIMP) tumors. Thus, we propose to create a Research Team under the guidance of two PIs, William Grady and Sanford Markowitz, to lead an EDRN Biomarker Developmental Lab to discover novel methylated genes that can be used as early detection markers and predictive markers using cutting-edge and complementary approaches, HumanMethylation27 DNA Analysis Beadchip (lllumina Infinium platform), and deep sequencing of captured NaHSO3 treated DNA (Agilent and Solexa). These approaches will take advantage of the developed expertise of the Grady lab and of the Markowitz lab, respectively, and have the potential to identify a panel of complementary biomarkers for the early detection of colorectal neoplasms and for enhancing the care of early stage CRC. We propose the following Specific Aims:
Aim 1) To develop and validate epigenetic signatures of colon adenomas and early stage non-metastatic colon cancers.
Aim 2) To perform a comprehensive epigenomic characterization of colorectal cancer molecular subtypes. 2a) To develop differential methylation profiles between CIMP and nonCIMP CRCs. 2b) To develop differential methylation profiles between CIN vs. MSI CRCs.
Aim 3) To identify and characterize biologically relevant novel methylation targets in colorectal cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA152756-02
Application #
8133476
Study Section
Special Emphasis Panel (ZCA1-SRLB-C (M1))
Program Officer
Wagner, Paul D
Project Start
2010-08-25
Project End
2015-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
2
Fiscal Year
2011
Total Cost
$584,114
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Venkitachalam, Srividya; Guda, Kishore (2017) Altered glycosyltransferases in colorectal cancer. Expert Rev Gastroenterol Hepatol 11:5-7
Morris, Shelli M; Davison, Jerry; Carter, Kelly T et al. (2017) Transposon mutagenesis identifies candidate genes that cooperate with loss of transforming growth factor-beta signaling in mouse intestinal neoplasms. Int J Cancer 140:853-863
Markowitz, Sanford D (2017) Cancer bypasses the lymph nodes. Science 357:35-36
Yuan, Zixu; Baker, Kelsey; Redman, Mary W et al. (2017) Dynamic plasma microRNAs are biomarkers for prognosis and early detection of recurrence in colorectal cancer. Br J Cancer 117:1202-1210
Luebeck, E Georg; Curtius, Kit; Hazelton, William D et al. (2017) Identification of a key role of widespread epigenetic drift in Barrett's esophagus and esophageal adenocarcinoma. Clin Epigenetics 9:113
Cohen, Stacey A; Yu, Ming; Baker, Kelsey et al. (2017) The CpG island methylator phenotype is concordant between primary colorectal carcinoma and matched distant metastases. Clin Epigenetics 9:46
Kim, Jaeil; Do, Eun-Ju; Moinova, Helen et al. (2017) Molecular Imaging of Colorectal Tumors by Targeting Colon Cancer Secreted Protein-2 (CCSP-2). Neoplasia 19:805-816
Williams, Christina D; Grady, William M; Zullig, Leah L (2016) Use of NCCN Guidelines, Other Guidelines, and Biomarkers for Colorectal Cancer Screening. J Natl Compr Canc Netw 14:1479-1485
Curtius, Kit; Wong, Chao-Jen; Hazelton, William D et al. (2016) A Molecular Clock Infers Heterogeneous Tissue Age Among Patients with Barrett's Esophagus. PLoS Comput Biol 12:e1004919
Anderson, Sarah; Poudel, Kumud Raj; Roh-Johnson, Minna et al. (2016) MYC-nick promotes cell migration by inducing fascin expression and Cdc42 activation. Proc Natl Acad Sci U S A 113:E5481-90

Showing the most recent 10 out of 49 publications