Mutations in the p53 tumor suppressor gene are frequently identified in human neoplasms. These mutations may be associated with stabilization and, therefore, with overexpression of the p53 protein product as determined by immunohistochemical staining. Using a new antigen retrieval method and a polyclonal antibody to p53 (CM-1), the authors examined 48 formalin-fixed paraffin-embedded adenocarcinomas of the pancreas for overexpression of the p53 gene product. These 48 carcinomas were obtained from a series of patients with well-documented clinical histories and extensive follow-up. The carcinomas had been analyzed previously for K-ras gene mutations, tumor ploidy, and tumor proliferating index. Specific diffuse nuclear staining for the p53 protein was identified in 19 of the 48 (40%) infiltrating carcinomas examined. Focal or negative staining was seen in the remaining 29 cases (60%). In addition, 17 of the neoplasms contained synchronous in situ carcinomas; two (12%) of these displayed diffuse nuclear staining for the p53 protein. Overexpression of p53 was associated with aneuploidy (P = .05), which had been a poor prognosticator in this series of adenocarcinomas of the pancreas. Although overexpression of p53 appeared to be associated with poor prognosis (hazard ratio, 1.8; P = .07), this was not statistically significant. Overexpression of p53 was not significantly associated with K-ras oncogene mutations or tumor proliferating index. The authors conclude that overexpression of the p53 protein occurs frequently in invasive adenocarcinomas of the pancreas and in some in situ carcinomas, as well.

Summary~Mutation of the p53 gene is reported to be of prognostic importance in colorectal carcinomas. Immunohistochemical staining of the accumulated p53 gene product may be a simple alternative for p53 mutation analysis. Previous studies addressing the prognostic importance of p53 expression. however, yielded contradictory results. Therefore, we evaluated the importance of p53 expression as a marker for long-term prognosis in a well-characterised study population of 109 colorectal carcinomas. After antigen retrieval with target unmasking fluid (TUF). immunostaining of p53 was performed with both monoclonal antibody D07 and polyclonal antibody CMI. Objective quantification of the p53 signal was assessed by a computerised image analyser. p53 expression was higher in non-mucinous tumours than in mucinous tumours (p53 labelling index = 30% and 17% respectively, P = 0.05), and in metastatic tumours compared with non-metastatic tumours (p53 labelling index = 37% and 22% respectively, P = 0.05 Lane, 1992;Levine, 1992aLevine, , 1992bOren, 1992;Vogelstein and Kinzler, 1992). It is located on the short arm of chromosome 17 in the region 17pl3 and encodes a 53 kDa nuclear phosphoprotein that serves as a transcription factor El-Deiry et al., 1993). The p53 protein indirectly regulates cell growth and inhibits cells with mutagenic damage from entering the S-phase by arresting the cell cycle in GI, during which DNA repair can proceed.In colorectal cancer, p53 mutations are frequently accompanied by allelic loss of 17p (Baker et al., 1989;Rodrigues et al., 1990). Both p53 mutations and allelic deletion of 17p occur late in tumour progression (Baker et al., 1990) and are reported to have prognostic value after surgery (Kern et al., 1989;Laurent-Puig et al., 1992;Offerhaus et al., 1992; Hamelin et al., 1994 In the p53-tested cohort of 109 patients, there were 56 men and 53 women; the median age was 66 years (mean age 65 years, s.d. = 10 years, range 25-96 years). Twenty-two tumours were located in the caecum or ascending colon, eight in the transverse colon or splenic flexure, 46 in the descending colon or sigmoid and 33 tumours in the rectum. Tumours

Colorectal tumorigenesis evolves (Gut 1995; 36: 76-80)

Background-Sulindac regresses colorectal adenomas in patients with familial adenomatous polyposis (FAP), although the mechanism of polyp regression is unclear. Aims-To determine whether diVerences occur in alteration of rectal epithelial apoptotic index and expression of apoptosis related proteins in FAP patients treated with sulindac compared with placebo. Patients-Twenty one FAP patients; 12 had not undergone colectomy. Methods-Patients with FAP were treated with sulindac 150 mg orally twice a day for three months (n=10) or placebo (n=11). Colorectal polyp number was determined and biopsies of the normal rectal mucosa were performed before and after three months of treatment. Response to treatment and alteration of the apoptotic ratio (index in base of crypt divided by index in surface epithelium) were evaluated. Bcl-2, bax, p21/WAF-1, and p53 proteins were assessed semiquantitatively by immunohistochemistry. Results-Significant decreases in polyp number and in the apoptotic ratio were seen in patients treated with sulindac compared with controls. The mean percentage change in polyp number from baseline was −46% in the sulindac group and +13% in the placebo group (p=0.005). Mean percentage change in the apoptotic ratio was −8% and +25% in the sulindac and placebo treated patients, respectively (p=0.004). No diVerences in expression or compartmentalisation of apoptosis related proteins were noted between treatment groups. Conclusions-Sulindac regression of colorectal adenomas is accompanied by alteration of the rectal epithelial apoptotic ratio with relative increase in apoptosis in surface cells compared with the deeper crypt. The utility of the apoptotic ratio as an intermediate biomarker for colorectal tumorigenesis deserves further study. (Gut 1999;45:822-828)