Immunohistochemical patterns in rectal cancer: application of tissue microarray with prognostic correlations.
ABSTRACT We utilized the high-throughput tissue microarray method to characterize immunohistochemical expression patterns with correlations to prognosis in rectal cancer. Immunostaining for the markers Ki-67, Bcl-2, p53, EGFR, E-cadherin, beta-catenin, MLH1 and MSH2 was performed in 269 rectal cancers. Expression profiles were correlated to metastasis-free survival. Immunostaining revealed frequent upregulation and/or aberrant staining patterns for several of the markers, but Ki-67, p53, Bcl-2 and EGFR did not show any correlation to prognosis. However, reduced membranous staining for beta-catenin (p = 0.04), lack of cytoplasmic staining for beta-catenin (p = 0.04), reduced membranous staining for E-cadherin (p = 0.02) and lack of cytoplasmic staining for E-cadherin (p = 0.02) correlated with metastatic disease. Multivariate analysis including the factors Dukes' stage and tumor differentiation grade demonstrated increased risk of metastatic disease in tumors with lack of cytoplasmic staining for beta-catenin (HR = 3.1, p = 0.02), reduced membranous staining for beta-catenin (HR = 1.7, p = 0.06) and reduced membranous staining for E-cadherin (HR = 2.1, p = 0.06). Loss of MMR protein expression was confirmed to be a rare event in rectal cancer with loss of MLH1 staining in 3% and MSH2 in 1% of the tumors. The lack of prognostic information contributed by most of these markers suggests that single markers for prognosis may be of limited value in rectal cancer. However, altered expression of beta-catenin and E-cadherin correlated with metastatic disease, and these markers may have prognostic importance in rectal cancer.
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ABSTRACT: β-catenin plays a key role in the progression of colorectal cancer (CRC). However, its prognostic significance for patients with CRC remains controversial. Identical search strategies were used to search relevant literatures in the PubMed, Embase and Web of Science databases. The correlation between β-catenin expression and clinicopathological features and prognosis was analyzed. A total of 18 studies met the inclusion criteria, which comprised 3665 cases. Meta-analysis suggested that β-catenin overexpression in the nucleus was significantly associated with disease free survival (DFS) (n = 541 in 3 studies; HR = 1.87, 95% CI: 1.28-2.71; Z = 3.26; P = 0.001) and overall survival (OS) for CRC patients (n = 2630 in 10 studies; HR = 1.55, 95% CI: 1.12-2.14; Z = 2.62; P = 0.009). However, there was no significant association between β-catenin expression in the cytoplasm and OS (n = 1327 in 3 studies; HR = 1.04, 95% CI: 0.88-1.24, Z = 0.46, P = 0.643). The combined odds ratio (OR) of β-catenin in the nucleus indicated that β-catenin overexpression was associated with advanced stage CRC (n = 950 in 7 studies; OR = 0.71, 95% CI: 0.53-0.94; Z = 2.35; P = 0.019) and metastasis of CRC (n = 628 in 5 studies; OR = 0.49, 95% CI: 0.25-0.96, Z = 2.06, P = 0.039). β-catenin overexpression in the nucleus had no correlation with the tumor site (colon or rectum), differentiation grade, lymph node status or depth of invasion. The pooled ORs were 1.09 (95% CI: 0.41-2.91, Z = 0.18, P = 0.856), 1.27(95% CI: 0.76-2.10, Z = 0.92, P = 0.357), 0.71(95% CI: 0.46-1.09, Z = 1.58, P = 0.115) and 0.82(95% CI: 0.4-1.68, Z = 0.53, P = 0.594). This study showed that β-catenin overexpression in the nucleus, rather than in the cytoplasm, appeared to be associated with progress disease and a worse prognosis for CRC patients.PLoS ONE 01/2013; 8(5):e63854. · 3.73 Impact Factor
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ABSTRACT: Research towards biomarkers that predict patient outcome in colorectal cancer (CRC) is rapidly expanding. However, none of these biomarkers have been recommended by the American Association of Clinical Oncology or the European Group on Tumor Markers. Current staging criteria result in substantial under-and over-treatment of CRC patients. Evasion of apoptosis, a characteristic feature of tumorigenesis, is known to correlate with patient outcome. We reviewed the literature on immunohistochemistry-based studies between 1998 and 2011 describing biomarkers in this pathway in CRC and identified 26 markers. Most frequently described were p53, Bcl-2, survivin, and the Fas and TRAILR1 receptors and their ligands. None of the studies reviewed provided sufficient support for implementing a single marker into current clinical practice. This is likely due to the complex biology of this pathway. We suggest focusing on the combination of key markers within the apoptosis pathway that together represent an 'apoptotic tumor profile', which better reflects the status of this pathway in a tumor.Biomarkers in cancer. 01/2013; 5:13-29.
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ABSTRACT: Epithelial-mesenchymal transition (EMT) plays a crucial role in the progression and aggressiveness of colorectal carcinoma. E-cadherin is the best-characterized molecular marker of EMT, but its prognostic significance for patients with CRC remains inconclusive. Eligible studies were searched from the PubMed, Embase and Web of Science databases. Correlation between E-cadherin expression and clinicopathological features and prognosis was analyzed. Subgroup analysis was also performed according to study location, number of patients, quality score of studies and cut-off value. A total of 27 studies comprising 4244 cases met the inclusion criteria. Meta-analysis suggested that downregulated E-cadherin expression had an unfavorable impact on overall survival (OS) of CRC (n = 2730 in 14 studies; HR = 2.27, 95%CI: 1.63-3.17; Z = 4.83; P = 0.000). Subgroup analysis indicated that low E-cadherin expression was significantly associated with worse OS in Asian patients (n = 1054 in 9 studies; HR = 2.86, 95%CI: 2.13-3.7, Z = 7.11; P = 0.000) but not in European patients (n = 1552 in 4 studies; HR = 1.14, 95%CI: 0.95-1.35, Z = 1.39; P = 0.165). In addition, reduced E-cadherin expression indicated an unfavorable OS only when the cut off value of low E-cadherin expression was >50% (n = 512 in 4 studies; HR = 2.08, 95%CI 1.45-2.94, Z = 4.05; P = 0.000). Downregulated E-cadherin expression was greatly related with differentiation grade, Dukes' stages, lymphnode status and metastasis. The pooled OR was 0.36(95%CI: 0.19-0.7, Z = 3.03, P = 0.002), 0.34(95%CI: 0.21-0.55, Z = 6.61, P = 0.000), 0.49(95%CI: 0.32-0.74, Z = 3.02, P = 0.002) and 0.45(95%CI: 0.22-0.91, Z = 3.43, P = 0.001), respectively. This study showed that low or absent E-cadherin expression detected by immunohistochemistry served as a valuable prognostic factor of CRC. However, downregulated E-cadherin expression seemed to be associated with worse prognosis in Asian CRC patients but not in European CRC patients. Additionally, this meta-analysis suggested that the negative threshold of E-cadherin should be >50% when we detected its expression in the immunohistochemistry stain.PLoS ONE 01/2013; 8(7):e70858. · 3.73 Impact Factor