Expression of EZH2 and Ki-67 in colorectal cancer and associations with treatment response and prognosis

Abstract

BACKGROUND: Enhancer of zeste homologue 2 (EZH2) is a member of the Polycomb group of genes that is involved in epigenetic silencing and cell cycle regulation. METHODS: We studied EZH2 expression in 409 patients with colorectal cancer stages II and III. The patients were included in a randomised study, and treated with surgery alone or surgery followed by adjuvant chemotherapy. RESULTS: EZH2 expression was significantly related to increased tumour cell proliferation, as assessed by Ki-67 expression. In colon cancer, strong EZH2 expression (P ¼ 0.041) and high proliferation (X40%; P ¼ 0.001) were both associated with better relapse-free survival (RFS). In contrast, no such associations were found among rectal cancers. High Ki-67 staining was associated with improved RFS in colon cancer patients who received adjuvant chemotherapy (P ¼ 0.001), but not among those who were treated by surgery alone (P ¼ 0.087). In colon cancers stage III, a significant association between RFS and randomisation group was found in patients with high proliferation (P ¼ 0.046), but not in patients with low proliferation (P ¼ 0.26). Multivariate analyses of colon cancers showed that stage III (hazard ratio (HR) 4.00) and high histological grade (HR 1.80) were independent predictors of reduced RFS, whereas high proliferation indicated improved RFS (HR 0.55). CONCLUSION: Strong EZH2 expression and high proliferation are associated features and both indicate improved RFS in colon cancer, but not so in rectal cancer.

Vitamin D has wide regulatory effects on histone demethylase genes

“…a classical epigenetic view, the regulation of JMJD3 by 1,25(OH) 2 D 3 may be a mechanism to guarantee the correct activation of genes through the loss of the repressive H3K27me3 mark. Having in mind the requirement of JMJD3 expression for an adequate 1,25(OH) 2 D 3 action, the deregulation in human colon cancer of JMJD3 (downregulation) 37 and of the Polycomb gene EZH2 (overexpression) [74][75][76][77][78] may generate resistance to therapy with 1,25(OH) 2 D 3 and its analogs.…”

Enhancer of Zeste Homolog 2 Expression Is Associated With Metastasis and Adverse Clinical Outcome in Clear Cell Renal Cell Carcinoma: A Comparative Study and Review of the Literature

“…Table 5 shows a detailed summary of all published studies reporting the association of EZH2 at the protein level with the tumor's clinicopathologic characteristics and outcome in carcinomas of different organs. With a few exceptions, 50,89,93,96 most published reports show that EZH2 overexpression is associated with higher histologic grade, more advanced clinicopathologic stage, and/or a higher risk of lymph node or distant metastasis. * Taking AJCC TNM staging as an example, a large proportion of the published literature (26 of 33 reports) demonstrated that EZH2 overexpression was correlated with more locally advanced disease and/or higher risk of lymph node or distal metastasis, while the remaining 7 reports showed no difference of EZH2 labeling in tumors with different TNM staging (as summarized in Table 5 61 However, Wagener and colleagues 63 were able to demonstrate a strong association between EZH2 expression on the one hand and high Fuhrman grade, advanced tumor stage, regional lymph node metastasis, and distant metastasis on the other.…”

“…[15][16][17]19,24, This notwithstanding, conflicting studies exist that report either no prognostic value for EZH2 21,[89][90][91]93 or even an association with improved disease-free survival, 96 albeit to a more limited extent. Similarly, contradictory results have been reported in RCC: whereas Hinz et al 61 reported that the presence of elevated EZH2 mRNA levels is associated with low disease recurrence, Wagener et al 63 showed that patients with overexpression of EZH2 had decreased disease-specific survival.…”

Prognostic significance of S100A4 expression in stage II and III colorectal cancer: results from a population‐based series and a randomized phase III study on adjuvant chemotherapy

“…Samples for TMA construction were available for 409 of the 412 patients 20. In 39 cases, S100A4 staining was not technically successful, leaving a study population of 370 patients.…”

“…The construction of TMAs has been described previously 17, 20. Sections from the TMAs were immunostained using the Dako EnVision Flex+ detections system (Dako, Glostrup, Denmark) as described previously 21.…”