Colorectal cancer is the second leading cause of cancer-related death in the United States. Individuals with ulcerative colitis (UC) are at high risk for development of colorectal cancer, with an incidence approaching 30% after 30 years of disease. Ulcerative colitis is a chronic, idiopathic inflammatory disease of the colon with a peak onset between the ages of 15 and 40. Cancers in ulcerative colitis do not develop from a colonoscopically recognizable adenomatous polyp like that in sporadic colon cancer, but arise from flat dysplastic epithelium which is not usually colonoscopically distinguishable from adjacent nondysplastic mucosa. While previous studies suggest that both sporadic and UC-related colon cancer develop through the accumulation of genetic alterations, there is evidence that there are considerable differences between them in the type and timing of specific genetic events. In addition, there is evidence that genetic alterations may precede the development of histologically-defined dysplasia. This proposal is based on a model in which genomic instability is an early event in ulcerative colitis-related carcinogenesis, resulting in genetic aberrations. The applicant hypothesizes that: 1) Genetic changes occur prior to the development of histologically-defined dysplasia in ulcerative colitis-related carcinogenesis, and 2) Specific genetic events are selected for during the clonal expansion and progression of ulcerative colitis-related neoplasia. To test these hypotheses the applicant proposes to apply techniques of molecular cytogenetics, comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH), to archival UC-related cancer colectomy specimens to define the earliest and most important genetic changes in UC-related neoplasia. In addition, the role of DNA mismatch repair in this process will be defined. Genetic alterations in candidate genes on chromosome 18q, and other specific candidate genes and cell cycle control genes will be investigated. Studies defined in this proposal will result in a greater understanding of the earliest and most important genetic alterations that occur in UC-related neoplasia. These findings will likely be generalizable to other cancers that arise in an inflammatory field including gastric, esophageal (Barrett's) and bladder cancer. In addition, the proposed studies offer the prospect of developing an objective surveillance test based on molecular cytogenetic analysis of chromosomes for the early detection of UC-related neoplasia.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Mammalian Genetics Study Section (MGN)
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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Aust, Daniela E; Terdiman, Jonathan P; Willenbucher, Robert F et al. (2002) The APC/beta-catenin pathway in ulcerative colitis-related colorectal carcinomas: a mutational analysis. Cancer 94:1421-7
Terdiman, Jonathan P; Aust, Daniela E; Chang, Cornell G et al. (2002) High resolution analysis of chromosome 18 alterations in ulcerative colitis-related colorectal cancer. Cancer Genet Cytogenet 136:129-37
Aust, D E; Terdiman, J P; Willenbucher, R F et al. (2001) Altered distribution of beta-catenin, and its binding proteins E-cadherin and APC, in ulcerative colitis-related colorectal cancers. Mod Pathol 14:29-39
Aust, D E; Willenbucher, R F; Terdiman, J P et al. (2000) Chromosomal alterations in ulcerative colitis-related and sporadic colorectal cancers by comparative genomic hybridization. Hum Pathol 31:109-14
Korn, W M; Yasutake, T; Kuo, W L et al. (1999) Chromosome arm 20q gains and other genomic alterations in colorectal cancer metastatic to liver, as analyzed by comparative genomic hybridization and fluorescence in situ hybridization. Genes Chromosomes Cancer 25:82-90
Aust, D E; Baretton, G B; Waldman, F M et al. (1999) [Molecular carcinogenesis in ulcerative colitis-associated and sporadic colorectal carcinoma--differences and similarities] Verh Dtsch Ges Pathol 83:130-8
Willenbucher, R F; Aust, D E; Chang, C G et al. (1999) Genomic instability is an early event during the progression pathway of ulcerative-colitis-related neoplasia. Am J Pathol 154:1825-30