Studies on p53, BAX and Bcl-2 protein expression and microsatellite instability in stage III (UICC) colon cancer treated by adjuvant chemotherapy: major prognostic impact of proapoptotic BAX.

We evaluated the expression patterns of proapoptotic BAX, antiapoptotic Bcl-2 and p53, the proposed upstream effector of these molecules, as potential prognostic markers in UICC stage III colon cancer by immunohistochemical staining. To identify high-frequency microsatellite instability (MSI+) individuals, we performed single-strand conformation polymorphism-based analysis for BAT26. A total of 188 patients who had received 5-fluorouracil (5-FU)-based adjuvant chemotherapy (5-FU/folinic acid or 5-FU/levamisole) were enrolled. Median follow-up was 84.5 months. We found that BAX, Bcl-2 and p53 protein expressions were high or positive in 59, 70 and 50% of 188 cases, respectively. MSI+ tumours were detected in 9% of 174 evaluable patients. BAX or Bcl-2 was correlated with a higher degree of differentiation or left-sided tumours (P=0.01 or P=0.03, respectively); MSI was correlated with right-sided tumours (P<0.0001). In contrast to p53, Bcl-2, or MSI, low BAX, advanced pN category, low grade of differentiation and treatment with 5-FU/levamisole were univariately associated with poorer disease-free survival (DFS) (P=0.0005, P=0.001, P=0.005 and P=0.01, respectively) and poorer overall survival (OS) (P=0.002, P=0.0001, P=0.003 and P=0.02, respectively). Besides pN category and treatment arm, BAX was an independent variable related to both OS and DFS (P=0.003 and P=0.001, respectively). In both univariate and multivariate analysis, the p53-/BAX high in comparison with the p53+/BAX high subset conferred a significantly improved DFS (P=0.03 and P=0.03, respectively) as well as a marginally improved OS (P=0.07 and P=0.08, respectively). BAX protein expression may be of central significance for clinical outcome to 5-FU-based adjuvant chemotherapy in stage III colon cancer, and bivariate analysis of p53/BAX possibly may provide further prognostic evidence.

Molecular lesions in colorectal cancer: impact on prognosis? Original data and review of the literature.

BACKGROUND: In the Dukes' B and C stages of colorectal carcinoma there are considerable variations in the observed courses of the disease. Since post-operative chemotherapy in patients with Dukes' C (node-positive) colon carcinoma has been demonstrated to be effective in improving overall-survival, a more exact prognosis assessment gains additional significance and therapeutic relevance. DISCUSSION: One also hopes to derive improved prognostic factors from the clarification of the molecular pathogenesis. Because of its frequency and the accessibility and recognizability of its developmental stages colorectal carcinoma is among the best investigated of all solid tumors. Despite a multitude of suggested molecular candidate markers none of these changes has yet been able enter the everyday life of the clinic. However, it is to be expected that some of the molecular alterations presently discussed will gain importance before long in the clinical treatment of patients with colorectal carcinoma. CONCLUSION: Considering also our own findings, this review presents the latest developments in the scientific discussion of the tumor suppressor/oncogenes p53, k-ras, and DCC, biochemical determinants of the 5-fluorouracil metabolism, and defects of the DNA repair system.

Diagnostic significance of nuclear p53 expression in the surveillance of Barrett's esophagus--a longitudinal study.

The efficacy of currently performed surveillance in patients with Barrett's esophagus (BE) is substantially compromised by shortcomings of dysplastic lesions as diagnostic markers. The aim of this study was to evaluate the possible role of p53 protein expression as complementary method in the diagnosis of neoplastic transformation in BE. A longitudinal study was performed. 41 patients were enrolled. The median time of surveillance was 46 months. 234 archival paraffin blocks containing a total of 627 biopsies were retrieved. p53 protein immunostaining by application of the monoclonal antibody DO-1 was performed. The results of immunohistochemistry were compared with the exact histopathological diagnosis and grading of dysplasia (no dysplasia, indefinite for dysplasia, low-grade dysplasia, high-grade dysplasia, carcinoma). In merely four of 206 nondysplastic mucosal sites p53 expression was found. However, p53 expression was detected with increasing frequency in sites indefinite for dysplasia (2/9), specimens with low-grade dysplasia (9/15), high-grade dysplasia (3/3) and the one with a carcinoma. This study shows a close association of nuclear p53 protein expression to the process of neoplastic transformation in Barrett's epithelium. However, it apparently does not precede the appearance of dysplasia significantly. Thus, nuclear p53 expression as detected by immunohistochemistry may serve to confirm a suspected diagnosis of dysplasia in BE.

Influence of p53 status on prognosis in preoperatively irradiated rectal carcinoma.

BACKGROUND: Even when they are analogous in microscopic and macroscopic appearance, tumors vary in their response rates to radiotherapy. Cell culture and xenograft experiments with colorectal cell lines have demonstrated that wild-type p53 increases radiosensitivity. Hence, the authors investigated, in a well-defined population of patients treated at the same institution, whether p53 status was a prognostic factor in preoperatively irradiated rectal carcinoma patients. METHODS: The p53 status of rectal adenocarcinomas was examined immunohistochemically (with monoclonal antibody DO-1) in preirradiated biopsy samples (n = 100) and corresponding postirradiated resected specimens (n = 97). The mean follow-up was 73.2 months (median, 71.3 months; range, 4.3-157 months). Statistical analysis was performed using the SPSS program (SPSS, Chicago, IL). RESULTS: p53 protein expression was detected in 55 of 100 biopsy samples (> or = 5% nuclear staining). There was essentially no difference in p53 expression between biopsy samples and corresponding resected specimens (54 of 97 vs. 55 of 97). In univariate analysis, p53 immunoreactivity of biopsy samples did not correlate with age, gender, tumor location, TNM stage, pT category, pN category, or histologic grade. Unlike clinicopathologic variables, p53 expression did not have a statistically significant association with local recurrence free, disease free, or overall survival in either univariate (P = 0.91, 0.18, and 0.17, respectively) or multivariate analysis. CONCLUSIONS: In contrast to cell line studies, this immunohistochemical study demonstrates that p53 status is not useful as a prognostic marker in preoperatively irradiated rectal carcinoma.

Comparative analysis of histology, DNA content, p53 and Ki-ras mutations in colectomy specimens with long-standing ulcerative colitis.

Neoplastic progression in patients with chronic ulcerative colitis is characterized by the development of epithelial dysplasia, which is accompanied by genetic alterations. This study determined the time of onset of p53 and Ki-ras mutations as well as DNA aneuploidy during histological progression towards carcinoma. In all, 278 samples of 7 colectomy specimens were analyzed by flow cytometry, histology and single-strand conformation polymorphism analysis. Of the samples, 22% (61/278) were dysplastic and 43% (122/278) aneuploid, while 25% (71/278) showed p53 and 4% (11/278) Ki-ras mutations. The correlation between aneuploid status and p53 mutations varied among the patients. A strong correlation was noticed between histological progression from low-grade dysplasia to carcinoma and p53 mutations as well as DNA aneuploidy. Ki-ras mutations were found in 40% (2/5) of the carcinomatous samples. The correlation between p53 mutations and the histological status of the samples suggest the involvement of this genetic event in the development of colon cancer in patients with ulcerative colitis. In contrast to Ki-ras mutations, the appearance of p53 mutations is an early event. Therefore p53 analysis might be helpful in the classification of indefinite dysplasia and in the identification of patients at risk for cancer development. Further studies are necessary to detect the additional genetic alterations preceding the development of DNA aneuploidy.