ABSTRACT
We examined the association of one linked GC/AT polymorphism at p73 with the risk of colorectal cancer. In the present study, we investigated whether this polymorphism was related to the risk of colorectal cancer, and whether there were relationships between the polymorphism and LOH, protein expression or clinicopathological variables. The p73 genotypes were determined by PCR-restriction fragment length polymorphism in 150 Tunisians patients with colorectal cancer and in 204 healthy control subjects. Immunohistochemistry was performed on normal mucosa, primary tumour and metastasis. The frequencies of the genotypes were 52% for wild-type (GC/GC), 31% for heterozygotes (GC/AT) and 17% for variants (AT/AT) in patients, and 54%, 35% and 11% in controls, respectively. There were no significant differences of the frequencies of the three genotypes between the patients and controls (p = 0.11). We did not find any relationship of the genotypes with clinicopathological features of patients. We found that patients with the AT/AT genotype had a significantly worse clinical outcome than those with the GC/AT and GC/GC genotype. There were no significant differences between tumoural immunostaining of the total p73 and p73 polymorphism (p = 0.16). However, we found a significant difference between the expression profile of DeltaNp73 isoform and frequencies of the three genotypes (p = 0.0001). No LOH was observed at p73 locus. Our results suggest that the AT/AT genotype is significantly associated with poor prognosis in colorectal cancer. All these findings suggest that p73 polymorphism analysis may provide useful prognostic information for colorectal cancer patients.
Subject(s)
Adenocarcinoma/genetics , Colorectal Neoplasms/genetics , DNA-Binding Proteins/genetics , Genetic Predisposition to Disease , Nuclear Proteins/genetics , Polymorphism, Single Nucleotide/genetics , Tumor Suppressor Proteins/genetics , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Case-Control Studies , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Exons , Female , Gene Expression Profiling , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Loss of Heterozygosity , Male , Polymerase Chain Reaction , Polymorphism, Restriction Fragment Length , Retrospective Studies , Risk Factors , Tumor Protein p73 , TunisiaABSTRACT
INTRODUCTION: The protein p73 is the first identified homolog of the tumor suppressor gene p53, but its function in tumor development has not been established. Indeed, the results regarding the p73 implication in colorectal cancers is still controversial. AIM: We investigated whether the p73 is implicated in colorectal cancer, whether the p73 expression is related to prognosis and whether the p73 expression is correlated with p21-ras or p53. MATERIALS AND METHODS: We performed a comparative immunohistochemical analysis of p73, p53, and p21ras proteins in primary colorectal tumor with matched normal mucosa and metastasis from 204 patients with colorectal cancer. We correlated these expressions with clinicopathologic variables and we compared the different profiles between nonmucinous carcinoma and mucinous carcinoma. RESULTS: In this study, we did not find any correlation between p73 expression, sex, age, site, differentiation and stage. Overexpression of p73 was significantly correlated with infiltrating growth pattern (P<0.0001) and nonmucinous carcinoma (P<0.0001). Furthermore, frequency and intensity of p73 expression were marquedly increased from normal mucosa (26%), to primary tumors (75%) and to metastasis (97%). Furthermore, expression of p73 was also correlated with shorter survival period. The prognostic significance of p73 expression remained, even after adjustment for the clinical and pathologic variables. The p73 expression was positively correlated only with p21ras expression (P<0.0001). CONCLUSIONS: All these findings prove that p73 expression should be considered as a valuable poor prognostic marker. Our data also suggest that TP73 gene may play a role in colorectal carcinoma development.