Associations of beta-catenin alterations and MSI screening status with expression of key cell cycle regulating proteins and survival from colorectal cancer

Abstract

BackgroundDespite their pivotal roles in colorectal carcinogenesis, the interrelationship and prognostic significance of beta-catenin alterations and microsatellite instability (MSI) in colorectal cancer (CRC) needs to be further clarified. In this paper, we studied the associations between beta-catenin overexpression and MSI status with survival from CRC, and with expression of p21, p27, cyclin D1 and p53, in a large, prospective cohort study.MethodsImmunohistochemical MSI-screening status and expression of p21, p27 and p53 was assessed in tissue microarrays with tumours from 557 cases of incident CRC in the Malmö Diet and Cancer Study. Chi Square and Spearman’s correlation tests were used to explore the associations between beta-catenin expression, MSI status, clinicopathological characteristics and investigative parameters. Kaplan-Meier analysis and Cox proportional hazards modelling were used to assess the relationship between beta-catenin overexpression, MSI status and cancer specific survival (CSS).ResultsPositive MSI screening status was significantly associated with older age, female sex, proximal tumour location, non-metastatic disease, and poor differentiation, and inversely associated with beta-catenin overexpression. Beta-catenin overexpression was significantly associated with distal tumour location, low T-stage and well-differentiated tumours. Patients with MSI tumours had a significantly prolonged CSS in the whole cohort, and in stage III-IV disease, also in multivariable analysis, but not in stage I-II disease. Beta-catenin overexpression was associated with a favourable prognosis in the full cohort and in patients with stage III-IV disease. Neither MSI nor beta-catenin status were predictive for response to adjuvant chemotherapy in curatively treated stage III patients. P53 and p27 expression was positively associated with beta-catenin overexpression and inversely associated with MSI. Cyclin D1 expression was positively associated with MSI and beta-catenin overexpression, and p21 expression was positively associated with MSI but not beta-catenin overexpression.ConclusionsFindings from this large, prospective cohort study demonstrate that MSI screening status in colorectal cancer is an independent prognostic factor, but not in localized disease, and does not predict response to adjuvant chemotherapy. Beta-catenin overexpression was also associated with favourable outcome but not a treatment predictive factor. Associations of MSI and beta-catenin alterations with other investigative and clinicopathological factors were in line with the expected.Virtual slidesThe virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8778585058652609

A scoring system based on artificial neural network for predicting 10-year survival in stage II A colon cancer patients after radical surgery

“…However, the prognostic significance of β-catenin expression in CRC remains unclear. Previous studies as well as our study showed the worse survival outcome for patients with high expression of nuclear β-catenin [35, 36], whereas some showed that the high nuclear expression was associated with a better prognosis [37, 38], and other studies even failed to find any predictive value of nuclear β-catenin in CRC [39, 40]. Further studies are needed to verify the predictive value of β-catenin in CRC.…”

Nuclear expression and/or reduced membranous expression of β-catenin correlate with poor prognosis in colorectal carcinoma

“…A total of 6216 cases, based on 29 studies that revealed a relationship between nuclear β-catenin expression and pathological features or DFS/5-year OS, were investigated and their major clinical characteristics are summarized in Table 1. [14,15,18–21,25–47] In addition, 9 studies showed a relationship between cytoplasmic β-catenin expression and pathological features or OS [17,19–21,25,33,34,37,43] (Table 2). Thirteen studies were selected for analysis of the prognostic value of reduced β-catenin expression in the membrane of CRC [17,19–21,26,31,34,35,38,43,48–50] (Table 3).…”

“…[14–17] However, other studies did not present this association. [18,19] The variable and contradictory results were also observed regarding the correlation between the reduced membranous β-catenin expression and the prognosis in patients with CRC. [17,19–21] A previous analysis suggested that β-catenin overexpression in nucleus, rather than in cytoplasm, was associated with poor prognosis of CRC.…”

Prognostic Significance of β-Catenin, E-Cadherin, and SOX9 in Colorectal Cancer: Results from a Large Population-Representative Series

“…While some studies have reported worse outcome for patients with low expression of β-catenin in the nucleus and other compartments (27–30), others have reported no difference in prognosis (26, 31, 43), and yet others have found that strong expression is associated with poor outcome (22, 32–34). The literature on E-cadherin is also marked by conflicting results, where some groups have reported no prognostic effect of altered E-cadherin expression (35, 36), whereas others have reported that patients with low E-cadherin expression have a poor prognosis (37, 38, 58).…”