We have developed unique methodology which permits quantitation of expression of each of many thousands of cDNA sequences in small biopsies taken from the human colonic mucosa. We have used this method to identify 8 sequences, one of which is subunit 3 of mitochondrial cytochrome c oxidase, whose level of expression changes in progression from normal mucosa to benign adenoma and on to colon carcinoma and whose expression is returned to the level characteristic of the normal mucosa when colon carcinoma cells are induced to differentiate in vitro. In addition, we have determined that high risk polyposis mucosa involves changes in expression of a far greater number of sequences. 29 clones were identified each of whose level of expression provides good discrimination between genetically high risk familial polyposis mucosa and genetically ow risk mucosa. Detection of risk has important practical implications for early detection and prevention. In addition, genetic and other predisposing risk for colon cancer may be more important in the development of colon cancer in the general population than previously appreciated. However, the mucosa at risk is essentially indistinguishable from normal mucosa. We therefore propose to study normal appearing mucosa from three genetic population groups identified epidemiologically as at risk for colorectal cancer (familial colon cancer families, heriditary non-polypotic colon cancer, and Utah pedigrees) and quiescent flat mucosa from patients with ulcerative colitis of >10 years duration. We will use the methodology we have developed and the clones identified, as well as analysis of expression of the genes for EGF, the EGFr, TGFa and the laminin receptor to identify a panel of sequences which can distinguish between genetically low risk flat mucosa and high risk, and amongst the high risk groups. Specific sequences will be selected from expression vector libraries we have made, analyzed further, and antisera developed to the encoded protein to study the changes in expression at the cellular level in biopsy tissue.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA041372-05
Application #
3181798
Study Section
Pathology B Study Section (PTHB)
Project Start
1986-09-30
Project End
1992-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
5
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Montefiore Medical Center (Bronx, NY)
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10467
Augenlicht, L H; Heerdt, B G (1992) Modulation of gene expression as a biomarker in colon. J Cell Biochem Suppl 16G:151-7
Augenlicht, L H; Taylor, J; Anderson, L et al. (1991) Patterns of gene expression that characterize the colonic mucosa in patients at genetic risk for colonic cancer. Proc Natl Acad Sci U S A 88:3286-9
Heerdt, B G; Molinas, S; Deitch, D et al. (1991) Aggressive subtypes of human colorectal tumors frequently exhibit amplification of the c-myc gene. Oncogene 6:125-9
Heerdt, B G; Augenlicht, L H (1991) Effects of fatty acids on expression of genes encoding subunits of cytochrome c oxidase and cytochrome c oxidase activity in HT29 human colonic adenocarcinoma cells. J Biol Chem 266:19120-6
Heerdt, B G; Augenlicht, L H (1990) Absence of detectable deletions in the mitochondrial genome of human colon tumors. Cancer Commun 2:109-11
Heerdt, B G; Augenlicht, L H (1990) Changes in the number of mitochondrial genomes during human development. Exp Cell Res 186:54-9
Heerdt, B G; Halsey, H K; Lipkin, M et al. (1990) Expression of mitochondrial cytochrome c oxidase in human colonic cell differentiation, transformation, and risk for colonic cancer. Cancer Res 50:1596-600
Augenlicht, L H; Wahrman, M Z; Halsey, H et al. (1987) Expression of cloned sequences in biopsies of human colonic tissue and in colonic carcinoma cells induced to differentiate in vitro. Cancer Res 47:6017-21
Augenlicht, L H; Augeron, C; Yander, G et al. (1987) Overexpression of ras in mucus-secreting human colon carcinoma cells of low tumorigenicity. Cancer Res 47:3763-5