Epigenetic deregulation of multiple S100 gene family members by differential hypomethylation and hypermethylation events in medulloblastoma

• Published in: British journal of cancer Vol. 97; no. 2; pp. 267 - 274
• Main Authors: LINDSEY, J. C, LUSHER, M. E, ANDERTON, J. A, GILBERTSON, R. J, ELLISON, D. W, CLIFFORD, S. C
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 10.07.2007
• Subjects: Adolescent; Adult; Azacitidine - analogs & derivatives; Azacitidine - pharmacology; Biological and medical sciences; Cancer research; Cell cycle; Cell Line, Tumor; Cerebellar Neoplasms - genetics; Cerebellum - metabolism; Child; Child, Preschool; DNA Methylation; DNA Modification Methylases - antagonists & inhibitors; Epigenesis, Genetic; Epigenetics; Female; Gene Expression Regulation, Neoplastic; Genes; Genetics and Genomics; Genomics; Humans; Infant; Male; Medical research; Medical sciences; Medulloblastoma - genetics; Metastasis; Neurology; Neurosciences; Proteins; S100 Proteins - genetics; Tumors; Tumors of the nervous system. Phacomatoses; United Kingdom > UK; Nervous system diseases; Cancerology; Medulloblastoma; Central nervous system disease; hypermethylation; hypomethylation; Epigenetics; S100; Multigene family; Malignant tumor; Methylation; Cerebral disorder
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6603852

Deregulated expression of genes encoding members of the S100 family of calcium-binding proteins has been associated with the malignant progression of multiple tumour types. Using a pharmacological expression reactivation approach, we screened 16 S100 genes for evidence of epigenetic regulation in medulloblastoma, the most common malignant brain tumour of childhood. Four family members (S100A2, S100A4, S100A6 and S100A10) demonstrated evidence of upregulated expression in multiple medulloblastoma cell lines, following treatment with the DNA methyltransferase inhibitor, 5'-aza-2'-deoxycytidine. Subsequent analysis revealed methylation of critical CpG sites located within these four genes in an extended cell line panel. Assessment of these genes in the non-neoplastic cerebellum (from which medulloblastomas develop) revealed strong somatic methylation affecting S100A2 and S100A4, whereas S100A6 and S100A10 were unmethylated. Assessed against these normal tissue-specific methylation states, S100A6 and S100A10 demonstrated tumour-specific hypermethylation in medulloblastoma primary tumours (5 out of 40 and 4 out of 35, respectively, both 12%) and cell lines (both 7 out of 9, 78%), which was associated with their transcriptional silencing. Moreover, S100A6 hypermethylation was significantly associated with the aggressive large cell/anaplastic morphophenotype (P=0.026). In contrast, pro-metastatic S100A4 displayed evidence of hypomethylation relative to the normal cerebellum in a significant proportion primary tumours (7 out of 41, 17%) and cell lines (3 out of 9, 33%), which was associated with its elevated expression. In summary, these data characterise complex patterns of somatic methylation affecting S100 genes in the normal cerebellum and demonstrate their disruption causing epigenetic deregulation of multiple S100 family members in medulloblastoma development. Epigenetic events affecting S100 genes have potential clinical utility and merit further investigation as molecular biomarkers for this disease.