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Targets of Discovery
Tissue-specific fingerprints - The first and crucial step in molecular classification of cancer is the establishment of tissue-specific expression patterns. An initial set of tissue-specific fingerprints will be obtained by microarray profiling of tumor specimen from a number of different organs. These fingerprints will then be used to classify liver metastases in cases where traditional methods have failed to identify the primary site of the tumor (clinically classified as 'unknown primary' cases).Tumor progression fingerprints - Based on tumor morphology, colon cancers have been classified into four stages. Tumor progression through these stages results in poor patient prognosis (Table 1).
Table 1
| Tumor Stage | Characteristics | 5-Year Survival |
| Dukes' A | Cancer is limited to the lining of the colon (mucosa or submucosa). | 80-90% |
| Dukes' B | Tumor invades through muscularis propria into the serosa, invades nearby organs. | 70-80% |
| Dukes' C | Regional metastasis of lymph nodes. | 30-55% |
| Dukes' D | Distant metastases to organs like liver, ovaries, lung and brain. | <5% |
Morphological classification often fails to accurately predict clinical outcome. However, there are a number of distinct genetic changes associated with the disease progression that may provide better prognostic and diagnostic tools. We are hoping to capture these genetic markers in a set of stage-specific gene-expression fingerprints.
APC - The adenomatous polyposis (APC) tumor-suppressor gene is mutated in 95% of colon cancers. Inactivation of APC function underlies both tumor initiation and promotion. We are performing gene expression profiling of tumor tissues from the four stages of colon cancer (Dukes' A-D), colon cancer cell lines, and a mouse model (APCMin mouse) to identify APC-induced genes.
p53 - The p53 tumor-suppressor gene integrates a number of signals that control cell life and death. p53 malfunction, due to mutations in either p53 or genes whose products transmit information from and to p53, is associated with nearly all human cancers. The goal of this project is to identify genes directly involved in p53-mediated signaling that may in the future serve as prognostic and diagnostic markers. Initial microarray studies will use cancer cell lines transfected with a temperature-sensitive p53 construct.
