Prognostic importance of p53 codon 72 polymorphism differs with race in microsatellite stable colorectal adenocarcinoma

PR-11

Background: We reported an increased incidence of mortalityfor African-Americans with colonic adenocarcinomas but not withrectal adenocarcinomas when compared to Caucasians (Cancer 2004; 101:66-76);moreover, this disparity was due to high-grade colorectal adenocarcinomas (CRCs) (Cancer2005; 103:2163-70). To understand the molecular basis for thisdisparity, the current preliminary study assessed the mutationalpatterns of the p53 gene in microsatellite (MS) stable CRCs collected from African-American and non-HispanicCaucasian patients and correlated with their survival.
 Materialsand Methods: We selected MS stable CRCs from 86 African-Americans and 119 Caucasians which were previously evaluated for the MS status.None ofthese patients have received any pre- or post-surgery adjuvanttherapies. The status of the p53 gene was assessed by directsequencing of the entire coding region (exons 2 through 11),using exon-specific primers. We used the Chi-square test to comparebaseline characteristics and Univariate Kaplan-Meier survivalanalyses to assess the prognostic significance of codon 72 polymorphism of the p53 gene based on race/ethnicity.
 Results: Overall, p53 missense mutations were observed in 53 of 205 (26%) MS stable CRCs, and the incidence of these mutations were similar in African-Americans (18 of 86; 21%) and Caucasian patients (35 of 119; 29%). Analysis of the 72 codon polymorphism in these CRCs demonstrated a higher frequency of Arg/Pro phenotypes (109 of 205, 53%) than phenotypes Arg/Arg (70 of 205, 34%) or Pro/Pro (26 of 205, 13%). CRCs homozygous for the Pro/Pro (7 of 26; 27%) or Arg/Arg (25 of 70; 36%) phenotypes had significantly higher incidence of p53 missense mutations (p=0.04) compared to heterozygous for the Arg/Pro (21 of 109; 19%) phenotype. The incidence of homozygous mutant variants Pro/Pro was higher in African-American patients as compared to Caucasians (58% versus 42%); in contrast, the wild type variant (Arg/Arg) frequency was higher in Caucasians than African-Americans (74% versus 26%) (p=0.002). CRCs with Pro/Pro mutant phenotypes were significantly correlated with the proximal colon (p=0.039), nodal metastasis (p=0.036) and exhibited high grade differentiation (p=0.015). African-Americans with SNPsat codon 72 which exhibit the phenotypes, Pro/Pro had higher mortality (median survival of 5 months) than those withthe phenotype Arg/Arg (median survival of 35 months) or Arg/Pro (median survival of 52 months) (overall, log-rank, P=0.046),such a difference in mortality was not observed in Caucasianpatients (overall, log-rank, P=0.686).
 Conclusions: These preliminaryfindings suggest that in MS stable CRCs the SNP pattern at codon 72 of the p53gene and their prognostic value differs in African-American and Caucasian patients; specifically, the phenotypes Pro/Proof p53 are associated with poor clinical outcome of African-Americanpatients. These studies are supported by a NCI/NIH grant CA098932-01.