Expression of ras and p53, DNA ploidy and 5-phase fraction in human colorectal adenocarcinoma

• The accumulation of oncogene and anti-oncogene alterations play an important role in the development of colorectal adenocarcinomas. These specific gene alterations cause changes of DNA ploidy and cell proliferation and, in turn, DNA instability might lead to more genetic changes. In the present work, the expression of ras p21 (79 cases) and p53 protein (293 cases) was investigated by immunohistochemistry, and DNA ploidy and S-phase fraction (279 cases) were measured by flow cytometry on colorectal adenocarcinomas.Overexpression of ras p21, nuclear and cytoplasmic p53 were found in 58%, 39% and 25% of the tumours, respectively, while in normal colorectal cases, only 35% were ras positive and no case showed p53 staining. Overexpression of ras was significantly associated with a high S-phase fraction. The frequencies of ras and nuclear p53 staining tended to be increased in DNA non-diploid tumours compared with diploid tumours. Cytoplasmic p53 positive tumours were more common in the proximal colon, while DNA non-diploid tumours were more frequent in the distal colon and rectum. The intensity of ras staining was significantly related to grade of differentiation and increased from Dukes' stage A to C tumours. Cytoplasmic p53 staining increased from Dukes' stage A to D tumours. In multivtiriate survival analyses of patients with Dukes' stage A-C tumours, the prognosticsignificance of ras expression remained even after adjustment for both stage and DNA ploidy. Nuclear p53 and cytoplasmic p53 staining prognosticated clinical Outcome independent of stage, DNA ploidy and each other. DNA non-diploidy predicted an unfavourable survival irrespective of stage, nuclear and cytoplasmic p53 expression. A highS-phase fraction was significantly associated with poor survival in univariate analysis but not after adjustment for other prognostic factors. Analyses in subgroups of tumours showed that the prognostic importance of cytoplasmic p53 expressionwas greater in patients with DNA diploid tumours than in those with non·diploid tumours, and that DNA ploidy exhibited prognostic effect in patients with Dukes' stage B tumours as well as in those with stage C tumours. We conclude that immunohistochemistry and flow cytometry may be used to detect overexpression ofras p21, nuclear p53 and cytoplasmic p53 as wellas abnormal DNA content, and that these alterations may be implicated in different biological mechanisms of colorectal adenocarcinomas and provide important prognostic information.

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