p53 and Ki-ras as prognostic factors for Dukes' stage B colorectal cancer
Introduction
The clinical behaviour of colorectal cancer is highly variable. Amongst various clinicopathological parameters such as histological degree of differentiation, vascular invasion, mucin production, size and location of the tumour, tumour stage is the most significant prognostic indicator [1]. However, there is important heterogeneity within a single stage category since approximately 1/3 of patients with Dukes' stage B and 2/3 of patients with Dukes' stage C will die of recurrent disease [2]. Approximately one-third of all colorectal tumours are Dukes' stage B and as yet, there are no parameters available allowing the subdivision of this group of patients into more accurate prognostic strata and no marker to reliably predict which patients are likely to benefit from adjuvant therapy.
It is now widely accepted that colonic carcinogenesis is a multistep process in which multiple mutational events, including activation of Ki-ras, inactivation of adenomatous polyposis coli (APC), deleted in colorectal cancer (DCC), TP53 and inactivation of DNA mismatch repair genes are implicated.
Ki-ras mutations occur early in colorectal carcinogenesis, mostly before adenoma formation, whereas TP53 mutations are implicated in the progression from adenoma to carcinoma. In colorectal cancers, the TP53 gene often shows missense mutations in one allele, accompanied by loss of the wild-type allele [3]. These missense mutations result in mutant p53 proteins with a prolonged half-life, which renders them detectable by immunohistochemical analysis 3, 4, 5. For as much as mutational events are the driving force in the process of colonic carcinogenesis, the hypothesis that the profile of mutations in a particular cancer would predict its behaviour seems justified. However, since the reported results of such studies are very contradictory, the impact of cancer associated gene mutations on the prognosis of colorectal carcinoma is still unresolved. Indeed, some studies showed that TP53 aberrations and Ki-ras mutations were not correlated with prognosis [6] whereas other studies indicated that mutations of these genes correlated with poor prognosis 7, 8, 9, 10. In contrast, Dix and colleagues observed that patients whose tumours showed p53 protein expression by immunohistochemistry had a significantly better prognosis than those whose tumours had no p53 immunoreactivity [4]. Part of this controversy might stem from the fact that in most reported series rather heterogeneous patient groups were studied. We, therefore, examined a large retrospective but clinically and therapeutically homogeneous, series of primary Dukes' stage B colorectal carcinomas, addressing the question of whether Ki-ras mutations and/or TP53 aberrations, as detected by molecular genetic analysis and immunohistochemistry, have any prognostic value in this group of patients.
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Patients
Patients who underwent curative surgical treatment performed between January 1985 and August 1989 at the Centre Hospitalier Universitaire Vaudois, Lausanne, for primary sporadic Dukes' stage B colorectal carcinoma, were enrolled in this study. Cases of inherited non-polyposis colorectal cancer, familial adenomatous polyposis or ulcerative colitis and patients who died in the immediate postoperative period were excluded from the study. Selected patient characteristics are presented in Table 1. A
p53 analysis
Immunohistochemical staining for p53 was carried out on a total of 122 cases. Normal mucosa samples were invariably negative for p53. p53 expression was detected in 57 (47%) colorectal adenocarcinomas (Table 1). The immunoreactivity was confined to the nuclei of neoplastic cells. Out of these 57 cases, 42 (74%) displayed a diffusely positive (++) pattern of immunoreactivity with more than 50% of positive tumour cells whereas 15 (26%) showed a partially positive (+) pattern where only 10–50% of
Discussion
Amongst the genetic abnormalities implicated in the development of colorectal cancer Ki-ras and TP53 mutations have probably been the most exhaustively studied [26]. Several studies reported that abnormalities of Ki-ras and/or TP53 genes correlate with a worse prognosis 7, 8, 9, 19, 22, 23. However, important discrepancies concerning the correlation of these parameters with the survival of colorectal carcinoma patients have emerged from the literature 6, 8, 20 with some studies showing no
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