Promoter Methylation of Wnt Inhibitory Factors and Expression Pattern of Wnt/beta-Catenin Pathway in Human Astrocytoma: Pathologic and Prognostic Correlations
Sun-A Kim, Shin Kwang Khang. University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
Background: Wnt inhibitory factor-1 (Wif-1) is an antagonist that inhibits Wnt signaling pathway. Thus, the functional loss of Wif-1 can contribute to tumorigenesis by activation of Wnt pathway. In this study, we investigated the contribution of Wif hypermethylation to the regulation of Wnt/beta-catenin signaling pathway, tumor grade and patient survival in astrocytoma.
Design: We selected 88 astrocytoma samples consisting of 20 diffuse astrocytomas (DA) and 66 glioblastomas (GB). For control sample, 17 temporal lobectomy specimens from patient with epilepsy were selected. DNA was extracted from paraffin-embedded tissue and ratio of methylated DNA to total methylated and unmethylated DNA (%methylation) was measured by methylation and unmethylation-specific PCR. Representitive tumor tissue was immunostained with Wif-1, beta-catenin, cyclin D1 and c-myc.
Results: The mean %methylation of tumor (DA and GB were significantly higher than in control brain tissue from temporal lobectomy. Significant negative correlation between %methylation and Wif-1-positive cell percentage was noted. Mean Wif-1 IHC score were lower in %methylation≥10 group than in %methylation<10 group. Cyclin D1 expression was higher in %methylation≥10 group (p=0.037). However, the staining pattern of beta-catenin and the intensity of c-myc staining were not related to Wif-1 propoter methylation level. Tumors with cytoplasmic or cytoplasmic-nuclear beta-catenin staining pattern was more frequently observed in tumors containing less than 50% of Wif-1 positive cells, and in tumors with lower IHC score. No significant relation between Wif-1 protein expression level and cyclin D1 and c-myc were found. On multivariate survival analysis, decreased Wif-1-positive cell percentage and Wif-1 IHC score were independently significant factors for poorer patient survival along with higher tumor grade, increased patient age and presence of residual tumor after resection.
Conclusions: Promoter methylation level of Wif-1 gene was increased in astrocytoma and may play a role in early stage of tumorigenesis by suppressing Wif-1 expression and increasing cyclin D1 expression. Decreased Wif-1 protein expression was associated with increased accumulation of cytoplasmic or cytoplasmic-nuclear beta-catenin and plays a key role in prognosis of patients with astrocytoma.
Tuesday, March 20, 2012 1:00 PM
Poster Session IV # 253, Tuesday Afternoon