Clinical implications ofSOCS1methylation in myelodysplastic syndrome

Abstract

SummaryThe 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 (47AE4%), and was more frequent in patients with high-risk MDS than in those with low-risk (52AE6% vs. 25AE8%, P ¼ 0AE011). SOCS1 methylation was closely associated with NRAS mutation (P ¼ 0AE010) and inversely associated with good-risk karyotype (P ¼ 0AE021). 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 (55AE8% vs. 27AE7% at 3 years, P ¼ 0AE004). This difference remained significant within the subgroup of patients with high-risk MDS (67AE3% vs. 45AE1% at 3 years, P ¼ 0AE045). 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.

Comparison of hypoplastic myelodysplastic syndrome (MDS) with normo-/hypercellular MDS by International Prognostic Scoring System, cytogenetic and genetic studies

“…Although AML1 and RAS mutations and SOCS-1 hypermethylation, all associated with poor survival, 7,24,40 occurred more frequently in NH-MDS patients than in h-MDS patients, the difference was not statistically significant, probably due to the limited number of patients studied. We think that more patients are needed to demonstrate the postulated difference.…”

“…Several hypotheses and models have been proposed for the pathogenesis of MDS, including flawed apoptosis, 5 hypermethylation of tumor suppressor genes such as p15, 6 and SOCS1 (suppressor of cytokine signaling-1), 7 which results in gene silencing, unbalanced differentiation and proliferation of progenitor cells, 8 and dysregulation of immune response. 9 Mutations of a lot of genes including AML1, 10 FLT3 11 and RAS 12,13 are all introduced into the elaboration of MDS mechanism, but their changes in h-MDS remain elusive.…”

Prognostic relevance of aberrant SOCS‐1 gene promoter methylation in myelodysplastic syndromes patients

“…Similarly, Wu et al . from Taiwan reported SOCS‐1 methylation in 47% of MDS cases. Comparable to the previous studies, the higher frequency of SOCS‐1 methylated in 31% cases of MDS was reported by Brakensiek et al .…”

MT1G Hypermethylation: A Potential Prognostic Marker for Hepatoblastoma

“…SOCS1 encodes a JAK-ligand protein, which regulates the cytosine-dependent signal transduction in the JAK/STAT pathway. The absence of SOCS could stimulate the kinase activity of JAK, promoting cell proliferation (38). The association between hypermethylation and transcriptional silencing of SOCS1 has already been reported in hepatoblastoma (12).…”