We reported previously a large multi-institutional trial implicating p53 mutations as being involved in the pathogenesis of Barrett's cancer and representing an early marker for the malignant potential of Barrett's epithelium.
Thus, overexpression of p53 occurs early in the malignant transformation of Barrett's and increases with histologic progression, and proliferation at the surface of Barrett's epithelium increases with progressive grades of dysplasia.
Mutations of p53 are clearly involved in the pathogenesis of Barrett's cancer for a subset of patients (46%), and the fact that we could detect mutations in premalignant Barrett's epithelium supports the hypothesis that p53 mutations may be a useful marker for patients at increased risk for development of invasive cancer.
We investigated the hypothesis that patients whose biopsies have increased 4N (G2/tetraploid) cell fractions are predisposed to progression to aneuploidy and determined the relationship between inactivation of p53 and the development of 4N abnormalities in Barrett's epithelium.
We conclude that both p53 and ras are implicated in the progression of Barrett's epithelium to invasive cancer, and that further clinical correlative studies are warranted to evaluate potential clinical application for such molecular markers.
Application of these findings to clinical problems include the identification of p53 mutations as markers for malignant change in Barrett's epithelium, the use of discordant p53 mutations to diagnose second primary malignant neoplasms in patients with head and neck cancer, and the potential for therapy by the reversal of genetic lesions.
However, the finding of p53 mutations in Barrett's epithelium adjacent to adenocarcinomas may have clinical implications for p53 as a premalignant marker for esophageal cancer.