Abundant hypermethylation of SOCS-1 in clinically silent pituitary adenomas

• Published in: Acta neuropathologica 2006-03, Vol.111 (3), p.264-271
• Main Authors: Buslei, Rolf, Kreutzer, Jürgen, Hofmann, Bernd, Schmidt, Verena, Siebzehnrübl, Florian, Hahnen, Eric, Eyupoglu, Ilker Y, Fahlbusch, Rudolf, Blümcke, Ingmar
• Format: Article
• Language: English
• Subjects: Adenoma - genetics; Adenoma - metabolism; Adolescent; Adult; Aged; Autopsies; Cloning; Craniopharyngioma - genetics; Craniopharyngioma - metabolism; Cytokines; DNA Methylation; DNA, Neoplasm - metabolism; Female; Gene Expression Regulation, Neoplastic; Gene Silencing; Growth factors; Growth hormones; Humans; Janus Kinases - physiology; Kinases; Male; Middle Aged; Neuropathology; Neurosurgery; Pituitary gland; Pituitary Neoplasms - genetics; Pituitary Neoplasms - metabolism; Proteins; Signal transduction; Signal Transduction - physiology; STAT Transcription Factors - physiology; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling Proteins - genetics; Suppressor of Cytokine Signaling Proteins - metabolism; Tumors
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-005-0009-9

Janus kinase (JAK)/signal transducers and activators of transcription (STAT) cascade are required for cytokines, growth factors, G-proteins and hormones (growth hormone and prolactin). Gatekeepers in this pathway are the suppressor of cytokine signalling (SOCS) family of proteins. Their expression level is epigenetically regulated by DNA methylation. We have investigated the CpG island methylation status of SOCS-1 in a cohort of pituitary adenomas (PA; n=57), craniopharyngiomas (CP; n=30) and normal pituitary tissue (NP; n=11) using methylation sensitive single-strand conformation polymorphism analysis (MS-SSCP) and direct sequencing. SOCS-1 hypermethylation was identified in 51% (29/57) of surgical specimens obtained from PA patients. 83% of these tumours were clinically silent. In contrast, no methylation of SOCS-1 was observed in CPs or NPs. Quantitative real-time PCR and western blot analysis confirmed reduced SOCS-1 expression in the majority of pituitary adenomas. The data is compatible with epigenetic silencing of the SOCS-1 gene and constitutive activation of the JAK-STAT pathway in PA. This appears to contribute particularly to those tumours characterized by a hormone-inactive status.