In a genome-wide screen using DMH (differential methylation hybridization) we have identified a CpG island within the 5 0 region and untranslated first exon of the secretory granule neuroendocrine protein 1 gene (SGNE1/7B2) that showed hypermethylation in low-and high-grade astrocytomas compared to normal brain tissue. Pyrosequencing was performed to confirm the methylation status of this CpG island in 89 astrocytic gliomas of different malignancy grades and six glioma cell lines. Hypermethylation of SGNE1/7B2 was significantly more frequent in diffuse low-grade astrocytomas as well as secondary glioblastomas and anaplastic astrocytomas as compared to primary glioblastomas. mRNA expression analysis by real-time RT-PCR indicates that SGNE1/7B2 expression is downregulated in astrocytic gliomas compared to white matter samples. Treatment of glioma cells with the demethylating agent 5-aza-2 0 -deoxycytidine restores the transcription of SGNE1/7B2. Overexpression of SGNE1/7B2 in T98G, A172 and U373MG glioblastoma cells significantly suppressed focus formation and led to a significant increase in apoptotic cells as determined by flow cytometric analysis in T98G cells. In summary, we have identified SGNE1/7B2 as a novel target silenced by DNA methylation in astrocytic gliomas. The high incidence of this alteration and the significant effects of SGNE1/7B2 on the growth and apoptosis of glioblastoma cells provide a first proof for a functional implication of SGNE1/7B2 inactivation in the molecular pathology of gliomas.Glioblastomas are the most frequent and most malignant tumors arising in the brain with a peak incidence between 45 and 70 years. 1 Despite recent therapeutic advances, these tumors respond poorly to radiation therapy and most forms of chemotherapy and retain a dismal prognosis with most patients dying within 1 year after diagnosis. Glioblastomas WHO Grade IV may develop through malignant progression from diffuse astrocytomas WHO Grade II or anaplastic astrocytomas WHO Grade III (secondary glioblastoma), but more frequently, de novo without evidence of a less malignant precursor lesion (primary glioblastoma). Several comprehensive profiling studies have uncovered a high incidence of genetic and epigenetic alterations in glioblastomas, some of which are specific for certain clinical glioblastoma subtypes. Primary glioblastomas frequently show loss of heterozygosity on chromosome 10q (70% of cases), EGFR amplification (36%), p16 (INK4a) deletion (31%) and PTEN mutations (25%). 2 Secondary glioblastomas as well as their lower grade precursor lesions exhibit frequent mutations of the TP53 and IDH1 genes. 2,3 Loss of genetic material from chromosome 10q25-qter is associated with both primary and secondary glioblastomas. 2 Promoter CpG island hypermethylation generally results in transcriptional silencing of associated genes and is crucial for the development of cancer. 4 Epigenetic alterations within promoter regions effect the binding affinity of transcription factors by interfering with transcription initiatio...