CpG island methylation and associated silencing is a frequent and early event in colorectal neoplasia. Some of the genes affected, such as MLH1 and p 16, clearly contribute physiologically to the neoplastic phenotype. We now propose the hypothesis that aberrant CpG island methylation will also contribute to the metastatic process in colon carcinoma. By extension, we suggest that identification of CpG islands specifically hypermethylated in metastatic lesions, or primary tumors prone to metastasis, will lead to genes and pathways physiologically involved in the metastasis process. We also propose that the presence of these methylation events in primary tumors will portend a poor prognosis. To test these hypotheses, we propose the following specific aims; (1) To clone CpG islands differentially methylated in metastatic tumors compared to primary tumors, as well as in paired metastatic/non-metastatic primary tumors from patients matched for clinicopathologic characteristics. CpG island cloning will be done using MCA/RDA, a technique developed in this laboratory and verified in multiple tumor types. Current data suggests that 50% of recovered clones are in the promoter of identifiable genes, thus vaIidating this approach for identification of silenced genes and pathways. (2) To screen primary tumors for aberrant methylation of the most promising clones, and relate methylation to prognosis in a group of tumors well characterized genetically and epigenetically. (3) To begin exploring the function of recovered genes using in-vitro transfection experiments. Successful completion of this project will lead to a better understanding of the metastatic process in colon cancer, better evaluation of the metastatic potential of primary tumors, new markers of prognosis in colon cancer and will lay the groundwork for the use of methylation inhibitors in the prevention and treatment of metastasis in colorectal neoplasia.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA098006-01A2
Application #
6811632
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Ault, Grace S
Project Start
2004-09-01
Project End
2009-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
1
Fiscal Year
2004
Total Cost
$278,595
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Tahara, Tomomitsu; Yamamoto, Eiichiro; Suzuki, Hiromu et al. (2014) Fusobacterium in colonic flora and molecular features of colorectal carcinoma. Cancer Res 74:1311-8
Tahara, Tomomitsu; Yamamoto, Eiichiro; Madireddi, Priyanka et al. (2014) Colorectal carcinomas with CpG island methylator phenotype 1 frequently contain mutations in chromatin regulators. Gastroenterology 146:530-38.e5
Tahara, Tomomitsu; Maegawa, Shinji; Chung, Woonbok et al. (2013) Examination of whole blood DNA methylation as a potential risk marker for gastric cancer. Cancer Prev Res (Phila) 6:1093-100
Estécio, Marcos R H; Gallegos, Juan; Dekmezian, Mhair et al. (2012) SINE retrotransposons cause epigenetic reprogramming of adjacent gene promoters. Mol Cancer Res 10:1332-42
Zhang, Yan; Shu, Jingmin; Si, Jiali et al. (2012) Repetitive elements and enforced transcriptional repression co-operate to enhance DNA methylation spreading into a promoter CpG-island. Nucleic Acids Res 40:7257-68
Ahn, Joong Bae; Chung, Woon Bok; Maeda, Osamu et al. (2011) DNA methylation predicts recurrence from resected stage III proximal colon cancer. Cancer 117:1847-54
Watanabe, Yoshiyuki; Castoro, Ryan J; Kim, Hyun Soo et al. (2011) Frequent alteration of MLL3 frameshift mutations in microsatellite deficient colorectal cancer. PLoS One 6:e23320
Konishi, Kazuo; Watanabe, Yoshiyuki; Shen, Lanlan et al. (2011) DNA methylation profiles of primary colorectal carcinoma and matched liver metastasis. PLoS One 6:e27889
Maegawa, Shinji; Hinkal, George; Kim, Hyun Soo et al. (2010) Widespread and tissue specific age-related DNA methylation changes in mice. Genome Res 20:332-40
Estécio, Marcos R H; Gallegos, Juan; Vallot, Céline et al. (2010) Genome architecture marked by retrotransposons modulates predisposition to DNA methylation in cancer. Genome Res 20:1369-82

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