Purpose MicroRNAs (miRNAs) have potential prognostic value for colorectal cancers (CRCs); however, their value based on patient race/ethnicity and pathologic stage has not been determined. The goal was to ascertain the prognostic value of 5 miRNAs with increased expression in CRCs of African American (Black) and non-Hispanic Caucasian (White) patients. Experimental Design TaqMan® qRT-PCR was used to quantify expression of miR-20a, miR-21, miR-106a, miR-181b, and miR-203 in paired normal and tumor CRC archival tissues collected from 106 Black and 239 White patients. The results were correlated with overall survival based on patient race/ethnicity and pathologic stage. Since decisions regarding adjuvant therapy are important for Stage III CRCs, and since miR-181b appeared to have prognostic value only for Stage III Black patients, we assessed its prognostic value in a separate cohort of Stage III CRCs of Blacks. Results All 5 miRNAs had higher expression in CRCs (>1.0-fold) than in corresponding normal tissues. High expression of miR-203 was associated with poor survival of Whites with Stage IV CRCs (HR=3.00, 95% CI=1.29–7.53), but in Blacks it was an indicator of poor survival of patients with Stage I and II CRCs (HR=5.63, 95% CI=1.03–30.64). Increased miR-21 expression correlated with poor prognosis for White Stage IV patients (HR=2.50, 95% CI=1.07–5.83). In both test and validation cohorts, high miR-181b expression correlated with poor survival of only Black patients with Stage III CRCs (HR=1.94, 95% CI=1.03–3.67). Conclusion These preliminary findings suggest that the prognostic value of miRNAs in CRCs varies with patient race/ethnicity and stage of disease.

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 from137 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 χ2 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 orArg/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.

BACKGROUND: Mucin 4 (MUC4) is aberrantly expressed in colorectal adenocarcinomas (CRCs) but its prognostic value is unknown. METHODS: Archival tissue specimens collected from 132 CRC patients who underwent surgical resection without presurgery or postsurgery therapy were evaluated for expression of MUC4 by using a mouse monoclonal antibody and horseradish peroxidase. MUC4 expression levels were correlated with clinicopathologic features and patient survival. Survival was estimated by both univariate Kaplan-Meier and multivariate Cox regression methods. RESULTS: In both normal colonic epithelium and CRCs, MUC4 staining was localized primarily in the cytoplasm. The optimal immunostaining cutoff value (!75% positive cells and an immunostaining score !2.0), which was derived by using the bootstrap method, was used to categorize CRCs into groups of high expression (33 of 132 patients; 25%) or low expression (99 of 132 patients; 75%). Patients who had early stage tumors (stages I and II) with high MUC4 expression had a shorter disease-specific survival (log-rank; P ¼ .007) than patients who had with low expression. Patients who had advanced-stage CRCs (stages III and IV) did not demonstrate such a difference (logrank; P ¼ .108). Multivariate regression models that were generated separately for patients with early stage and advanced-stage CRC confirmed that increased expression of MUC4 was an independent indicator of a poor prognosis only for patients who had early stage CRCs (hazard ratio, 3.77; 95% confidence interval, 1.46-9.73). CONCLU-SIONS: The current results indicated that increased MUC4 expression is a predictor of poor survival in CRC, specifically for patients who have early stage tumors. Cancer 2010;116;3577-86.

A variety of genetic and molecular alterations underlie the development and progression of colorectal neoplasia (CRN). Most of these cancers arise sporadically due to multiple somatic mutations and genetic instability. Genetic instability includes chromosomal instability (CIN) and microsatellite instability (MSI), which is observed in most hereditary non-polyposis colon cancers (HNPCCs) and accounts for a small proportion of sporadic CRN. Although many biomarkers have been used in the diagnosis and prediction of the clinical outcomes of CRNs, no single marker has established value. New markers and genes associated with the development and progression of CRNs are being discovered at an accelerated rate. CRN is a heterogeneous disease, especially with respect to the anatomic location of the tumor, race/ethnicity differences, and genetic and dietary interactions that influence its development and progression and act as confounders. Hence, efforts related to biomarker discovery should focus on identification of individual differences based on tumor stage, tumor anatomic location, and race/ethnicity; on the discovery of molecules (genes, mRNA transcripts, and proteins) relevant to these differences; and on development of therapeutic approaches to target these molecules in developing personalized medicine. Such strategies have the potential of reducing the personal and socio-economic burden of CRNs. Here, we systematically review molecular and other pathologic features as they relate to the development, early detection, diagnosis, prognosis, progression, and prevention of CRNs, especially colorectal cancers (CRCs).

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.