Clinical implications of SOCS1 methylation in myelodysplastic syndrome

The suppressor of cytokine signalling-1 (SOCS1) protein is a tumour suppressor. Hypermethylation of SOCS1 gene, resulting in transcriptional silencing, is suggested to play an important role in cancer development. We sought to characterise SOCS1 methylation in primary myelodysplastic syndrome (MDS) and clarify its clinical implications. The methylation status of SOCS1 was analysed by methylation-specific polymerase chain reaction in 114 patients with primary MDS and serial studies were performed in 29 of them. SOCS1 methylation occurred in 54 patients (47.4%), and was more frequent in patients with high-risk MDS than in those with low-risk (52.6% vs. 25.8%, P = 0.011). SOCS1 methylation was closely associated with NRAS mutation (P = 0.010) and inversely associated with good-risk karyotype (P = 0.021). With a median follow-up of 17 months (range: 1-231 months), two patients acquired SOCS1 methylation during disease progression. In two patients, SOCS1 methylation present at diagnosis, disappeared after haematopoietic stem cell transplantation. Patients with SOCS1 methylation had a higher cumulative risk of leukaemic transformation than those without (55.8% vs. 27.7% at 3 years, P = 0.004). This difference remained significant within the subgroup of patients with high-risk MDS (67.3% vs. 45.1% at 3 years, P = 0.045). This is the first report to demonstrate the clinical relevance of SOCS1 methylation in MDS. It may play an important role in the pathogenesis of MDS, especially among patients with high-risk subtypes.