Prognostic significance of p53 codon 72 polymorphism differs with race in colorectal adenocarcinoma

Abstract

Purpose: Several studies have examined the prognostic value of the codon 72 polymorphism of the p53 gene in colorectal adenocarcinoma, but none have addressed patient race/ethnicity. Therefore, this study assessed the prognostic value of this polymorphism in African American and Caucasian colorectal adenocarcinoma patients separately.

Experimental design: Colorectal adenocarcinomas from 137 African Americans and 236 non-Hispanic Caucasians were assessed for p53 mutations and genotyped for the codon 72 polymorphism. The phenotypes were correlated with p53 mutational status, clinicopathologic features, and patient survival using the chi(2) test and Kaplan-Meier and Cox regression models.

Results: The incidence of p53 mutations was similar in African American and Caucasian patients (50% versus 54%, respectively); however, the homozygous Pro72 allele frequency was higher in African Americans (17%) as compared with Caucasians (7%). In contrast, the homozygous Arg72 allele frequency was higher in Caucasians (36%) than in African Americans (19%). In African Americans but not Caucasians, the Pro/Pro phenotype significantly correlated with a higher incidence of missense p53 mutations and with nodal metastasis. African Americans, but not Caucasians, with the Pro/Pro phenotype had significantly higher mortality (log-rank P = 0.005 versus. P = 0.886) and risk of death due to colorectal adenocarcinoma (hazard ratio, 2.15; 95% confidence interval, 1.02-4.53 versus hazard ratio, 1.60; 95% confidence interval, 0.69-3.18) than those with the phenotype Arg/Arg or Arg/Pro.

Conclusions: The higher frequency of the Pro/Pro phenotype of p53 in African American patients with colorectal adenocarcinoma is associated with an increased incidence of p53 mutations, with advanced tumor stage, and with short survival.

Fig. 1

PCR with PCR-restriction fragment length polymorphism (PCR-RFLP) and sequence analysis. Genotyping of p53 for the codon 72 polymorphism by PCR-RFLP. A, the 279-bp target DNA fragment, containing the CGC/CCC site of the p53 gene codon 72 located in exon 4, was digested with Bstu 1. The digested product was separated on a 3% agarose gel with ethidium bromide and photographed with an UltraViolet Product Image Store system.The C/C genotype (Pro/Pro phenotype) produced a single 299-bp band due to loss of the Bstu1restriction site; the wild-type G/G genotype (Arg/Arg phenotype) produced two bands (119-bp and 160-bp); and the G/C genotype (Arg/Pro phenotype) produced three bands (119-bp, 160-bp, and 279-bp). B, direct sequencing analysis of DNA fragments confirmed by PCR-RFLP.

Fig. 2

Kaplan-Meier survival curves for impact of p53 mutations and the codon 72 polymorphism based on race. For both African Americans (A, log-rank, P = 0.001) and Caucasians (B, log-rank, P = 0.028) colorectal cancers with p53 mutations had significantly poor survival compared with those with wild-type p53. C, African American patients with colorectal cancers having the mutant Pro/Pro phenotype of p53 had significantly poorer survival compared with those with the wild-type Arg/Arg phenotype or those heterozygous for the Arg/Pro phenotypes (log-rank, P = 0.005). D, for Caucasian patients, there was no survival difference between the codon 72 phenotypes of p53 (log-rank, P = 0.866).