Expression and prognostic significance of APAF‐1, caspase‐8 and caspase‐9 in stage II/III colon carcinoma: Caspase‐8 and caspase‐9 is associated with poor prognosis

Apoptosis protease activating factor‐1 (APAF‐1), caspase‐8 and caspase‐9 are important factors in the execution of death signals. To study their prognostic influence in colon carcinoma, expression of APAF‐1, caspase‐8 and caspase‐9 was determined by immunohistochemistry in normal colon mucosa (n = 8) and R0‐resected stage II/III colon carcinomas (n ≥ 124) using a semiquantitative score. Staining results were correlated with disease‐free survival by Kaplan–Meier estimates, and multivariate Cox analyses were performed. In normal colon, APAF‐1 and caspase‐8 are most strongly expressed in the luminal surface epithelium, whereas caspase‐9 is expressed all along the crypt axis. In colon carcinomas, there is considerable variability in the expression of these proapoptotic factors, although complete loss of caspase‐8 and caspase‐9 is rare. APAF‐1 expression did not correlate with disease‐free survival. Instead, both expression of caspase‐9 and high‐level expression of caspase‐8 in a majority of tumor cells were significantly associated with adverse prognosis (p = 0.004 and p = 0.029, respectively). The influence of caspase‐8 expression was mainly seen in patients with stage III colon carcinoma (p = 0.011), whereas the prognostic influence of caspase‐9 expression was significant in stage II cases (p = 0.037) and just failed to be significant in stage III tumors (p = 0.0581). After adjusting for confounding factors in a multivariate Cox analysis, the effect of caspase‐9 in predicting disease‐free survival was confirmed (p = 0.003). Our data suggest that, in colon carcinomas, expression of caspase‐8 and caspase‐9 is significantly associated with poor survival. Caspase‐9 may be an independent prognosticator in colon carcinoma.