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Although the prognostic value of  p53  abnormalities in Stage III microsatellite stable (MSS) colorectal cancers (CRCs) is known, the gene expression profiles specific to the  p53  status in the MSS background are not known. Therefore, the current investigation has focused on identification and validation of the gene expression profiles associated with p53 mutant phenotypes in MSS Stage III CRCs. Genomic DNA extracted from 135 formalin-fixed paraffin-embedded tissues, was analyzed for microsatellite instability (MSI) and  p53  mutations. Further, mRNA samples extracted from five p53-mutant and five p53-wild-type MSS-CRC snap-frozen tissues were profiled for differential gene expression by  Affymetrix Human Genome U133 Plus 2.0 arrays.  Differentially expressed genes were further validated by the high-throughput quantitative nuclease protection assay (qNPA), and confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and by immunohistochemistry (IHC). Survival rates were estimated by Kaplan-Meier and Cox regression analyses. A higher incidence of  p53  mutations was found in MSS (58%) than in MSI (30%) phenotypes. Both univariate (log-rank, P = 0.025) and multivariate (hazard ratio, 2.52; 95% confidence interval, 1.25–5.08) analyses have demonstrated that patients with MSS-p53 mutant phenotypes had poor CRC-specific survival when compared to MSS- p53  wild-type phenotypes. Gene expression analyses identified 84 differentially expressed genes. Of 49 down-regulated genes,  LPAR6 ,  PDLIM3 , and  PLAT , and, of 35 up-regulated genes,  TRIM29 ,  FUT3 ,  IQGAP3 , and  SLC6A8  were confirmed by qNPA, qRT-PCR, and IHC platforms.  p53  mutations are associated with poor survival of patients with Stage III MSS CRCs and  p53 -mutant and wild-type phenotypes have distinct gene expression profiles that might be helpful in identifying aggressive subsets.

Prognostic Significance and Gene Expression Profiles of p53 Mutations in Microsatellite-Stable Stage III Colorectal Adenocarcinomas