Abstract
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.
Highlights
For patients with colorectal cancers (CRCs), the presence of lymph node metastases is a factor in determining treatment modalities and for predicting clinical outcomes [1]
The prognostic value of p53 mutations in microsatellite stable (MSS) phenotypes of Stage III CRCs was assessed, and other molecular markers associated with p53 mutant phenotypes were identified
The prevalence of p53 mutations was higher in CRCs with the MSS phenotype (59%) as compared to the microsatellite instability (MSI)-H phenotype (30%)
Summary
For patients with colorectal cancers (CRCs), the presence of lymph node metastases is a factor in determining treatment modalities and for predicting clinical outcomes [1]. The chromosomal instability pathway accounts for 85% of sporadic CRCs [3]. These aggressive tumors are characterized by allelic losses at 17p and 18q and by the presence of mutations in common oncogenes and tumor suppressor genes [3,4]. Chromosomal abnormalities, such as aneuploidy, amplifications, and translocations, are common in familial CRCs [5]
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