CYTOPLASMIC ACCUMULATION OF P53 PROTEIN - AN INDEPENDENT PROGNOSTIC INDICATOR IN COLORECTAL ADENOCARCINOMAS

Background: Aberrations of the p53 gene (also known as TP53) frequentl y lead to the synthesis of mutant proteins that accumulate in the nucl ei and/or cytoplasm of neoplastic cells. Intracellular p53 protein acc umulation may be an unfavorable prognostic parameter in breast, lung, ovarian, gastric, and colorectal cancers. Specific classes of p53 gene mutations, assayed by characteristic subcellular p53 protein accumula tion patterns, may be useful prognostic indicators. Purpose: The progn ostic value of nuclear and cytoplasmic p53 protein accumulation in the tumor cells of patients with colorectal carcinoma was studied. Method s: Antibodies PAb 1801 and CM1 were used for immunocytochemical assay of nuclear and cytoplasmic p53 protein accumulation in a retrospective series of colorectal carcinoma samples obtained from 206 patients who were followed for at least 5 years. Results were correlated with the following clinicopathologic parameters: patient sex and age; tumor sit e, stage, and grade; and DNA ploidy status of the tumors. Overall surv ival and disease-free survival were analyzed with the Kaplan-Meier met hod. Differences in distributions were analyzed using the Mantel-Cox m ethod. Multivariate analysis was performed with the Cox proportional h azards model. Results: Immunostaining with PAb 1801 revealed nuclear p 53 accumulation in 46% (95) of 206 cases, whereas CM1 immunostaining o f 197 cases showed nuclear and cytoplasmic p53 accumulation in 33% (65 cases) and 50% (99 cases) of the cases, respectively. In univariate a nalysis, both nuclear p53(PAb 1801) and cytoplasmic p53(CM1) protein a ccumulations were significantly associated with poor overall survival (P = .0198 and P = .0017, respectively) and with disease-free survival (P = .004 and P = .0016, respectively). When patients were analyzed a ccording to site of their tumors, nuclear p53(PAb) 1801 protein accumu lation was statistically significant only in the right colon (P = .027 ), whereas cytoplasmic p53(CM1) protein accumulation was statistically significant in the left colon and rectum (P = .0016). In multivariate analysis, only cytoplasmic p53(CM1) protein accumulation was associat ed with poor overall survival and E with disease-free survival (P = .0 06 and P = .002, respectively). With the addition of DNA ploidy status , however, cytoplasmic p53(CM1) protein accumulation remained signific ant only for disease-free survival (P = .035). In patients with tumors of the left colon and rectum, cytoplasmic p53(CM1) protein accumulati on was the most significant prognostic indicator for overall survival (P = .007) and disease-free survival (P = .002) after disease stage. C onclusion: Cytoplasmic p53(CM1) protein accumulation, but not nuclear p53(PAb) (1801) protein accumulation, is an independent prognostic par ameter in patients with colorectal carcinomas. Implications: Cytoplasm ic p53(CM1) accumulation may be a useful indicator of patients at high risk for disease recurrence who may benefit from aggressive adjuvant therapy.