Prognostic values of radiation-induced p53 in adjacent normal mucosa and p21WAF1/CIP1 expression in rectal cancer patients

Abstract

DNA damage induces p53-mediated cell cycle arrest in which p21WAF1/CIP1, a cyclin-dependent kinase inhibitor, may play a critical role by being regulated via wild-type p53. Although adjuvant preoperative radiotherapy in rectal carcinoma is generally believed to improve the prognosis, it remains unclear which factors control the response. We investigated the interactions between the underlying mechanisms of cell cycle perturbation in response to radiotherapy, and local recurrence and distant metastasis in patients undergoing radical surgery for rectal carcinoma. A retrospective review was carried out in which 63 cases of Dukes' B or C, well or moderately differentiated rectal carcinomas in the lower two-thirds of the rectum, with or without preoperative radiotherapy, were immunohistochemically analyzed using antibodies to p53 and p21WAF1/CIP1. Induced p53 expression in adjacent normal mucosa, as seen in seven of 35 cases with radiotherapy, and mutually exclusive p21WAF1/CIP1 immunoreactivity, was strongly associated with local recurrence (P=0.0001). Furthermore, high p21WAF1/CIP1 expression was associated with a lack of distant metastasis (P=0.032). Our data suggest that there are some cases in which p53 overexpression in adjacent normal mucosa induced by radiotherapeutic treatment might heighten the risk of local recurrence, and that p21WAF1/CIP1 induction independent of the status of the p53 gene showing radiosensitivity might lead to a less distant metastasis.