Colorectal cancer is the second most common cause of cancer deaths in the US. A better understanding Of its pathOgenesis might lead to earlier diagnosis and/or prevention of this disease. Aberrant crypt foci (ACF) are the earliest identified putative precursors of colon cancer. They are identified microscopically in whole-mount specimens of colon. ACF are seen (a) in rodents as early as 2 weeks after a single dose of carcinogen and (b) in humans at increased frequency in patients with colon cancer. ACF are by definition grossly invisible but resemble some lesions identified at endoscopy and may include some small """"""""flat adenomas."""""""" The overall aim of these studies is to test the hypothesis that ACF are putative preneoplastic lesions in human colonic mucosa and that subpopulations of these lesions progress to colon cancer. The following studies will be carried out to test this hypothesis, i.e., that at least some ACF are neoplastic and not merely hyperplastic lesions. The expression of phenotypic markers thought to be related to neoplasia will be compared in histological sections of human ACF and """"""""flat adenomas."""""""" The phenotypic alterations to be examined as candidate markers for premalignant or malignant colonic epithelium include (a) the presence and degree of dysplasia, (b) carcinoembryonic antigen (CEA), (c) the adhesion molecule CD44, (d) mucin antigens, and (e) products of the suppressor genes APC and p53. Genetic alterations that are thought to occur early in the pathogenesis of colon cancer such as mutations in APC and K-ras genes and genomic instability will be determined in a larger number of ACF from patients with sporadic colon cancer with PCR-amplified DNA from microdissected tissue. When ACF have 15 or more crypts, a portion of the ACF will be embedded for the evaluation of dysplasia in longitudinal sections and the remaining portion will be microdissected for DNA amplification. ACF from patients (a) with sporadic colon cancer, (b) with familial polyposis, and (c) without colon cancer will be analyzed for clonality with X-linked chromosomal markers and molecular techniques after PCR. Chromosomal abnormalities detected with in situ DNA probes will be compared in ACF and """"""""flat adenomas."""""""" Specific characteristics of ACF and """"""""flat adenomas"""""""" in the whole-mount specimens will be correlated with the above findings and/or with dysplasia observed in these lesions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA066725-02
Application #
2008784
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1996-02-09
Project End
2000-11-30
Budget Start
1996-12-01
Budget End
1997-11-30
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Pathology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Chen, Wei-Dong; Han, Z James; Skoletsky, Joel et al. (2005) Detection in fecal DNA of colon cancer-specific methylation of the nonexpressed vimentin gene. J Natl Cancer Inst 97:1124-32
Pretlow, Theresa P; Pretlow, Thomas G (2005) Mutant KRAS in aberrant crypt foci (ACF): initiation of colorectal cancer? Biochim Biophys Acta 1756:83-96
Luo, Liping; Chen, Wei-dong; Pretlow, Theresa P (2005) CpG island methylation in aberrant crypt foci and cancers from the same patients. Int J Cancer 115:747-51
Pretlow, Theresa P; Edelmann, Winfried; Kucherlapati, Raju et al. (2003) Spontaneous aberrant crypt foci in Apc1638N mice with a mutant Apc allele. Am J Pathol 163:1757-63
Luo, Liping; Li, Biaoru; Pretlow, Theresa P (2003) DNA alterations in human aberrant crypt foci and colon cancers by random primed polymerase chain reaction. Cancer Res 63:6166-9
Li, Hui; Myeroff, Lois; Smiraglia, Dominic et al. (2003) SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers. Proc Natl Acad Sci U S A 100:8412-7
Hardy, R G; Tselepis, C; Hoyland, J et al. (2002) Aberrant P-cadherin expression is an early event in hyperplastic and dysplastic transformation in the colon. Gut 50:513-9
Hao, X P; Pretlow, T G; Rao, J S et al. (2001) Inducible nitric oxide synthase (iNOS) is expressed similarly in multiple aberrant crypt foci and colorectal tumors from the same patients. Cancer Res 61:419-22

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