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Promoter hypermethylation of Wnt pathway inhibitor SFRP1 gene and its expression levels in human astrocytomas

Background: Astrocytomas are the most common primary brain tumors that are on the basis of their histology, molecular characteristics and prognosis classified into 4 different malignancy grades. As one of the key oncogenic pathways in human malignancies that has been associated to many human cancers the Wnt signaling pathway has also been implicated in gliomagenesis. In the present study we aimed to identify the status of SFRP1 promoter hypermethylation in different malignancy grades of astrocytoma and assess its parallel expression levels in search for their connection with clinical data. Methods: Promoter hypermethylation of critical molecular component of Wnt signaling – SFRP1 was studied in 24 astrocytomas of different malignancy grades by using methylation-specific PCR (MSP). In order to examine the consequence of hypermethylation, the SFRP1 protein was investigated by immunohistochemistry and analyzed by quantitative stereological analysis. Results: SFRP1 promoter hypermethylation was found in 32% of astrocytomas. Hypermethylation of SFRP1 promoter was progressively rising in higher astrocytoma grades with the highest significant distribution in glioblastoma (P=0.042). The expression of SFRP1 protein showed 45.8% of cases with weak or lack of expression, 25% with moderate and 29.2% with strong expression levels. Our study showed that cases with methylated SFRP1 promoter expressed significantly less SFRP1 protein than unmethylated ones (P=0.031). Furthermore, we have shown that the levels of beta-catenin, pathways indicator of oncogenic activity, were elevated with often nuclear localization. Statistical analysis showed that glioblastoma samples with unmethylated SFRP1 promoter had significantly less beta-catenin (P=0.033). The activation of Wnt signaling was further confirmed by the expression of its transcriptional activators. Strong expression of LEF1 was significantly associated to higher grades (P=0.006). Conclusions: Our findings showed that SFRP1 acts as an antagonist in the evolution of astrocytoma which will contribute to better understanding of astrocytoma molecular profile and offer methylation biomarker of progression.

astrocytic brain tumors ; SFRP1 promoter hypermethylation ; transcription factors TCF1 and LEF1

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