SOCS1 Methylation Predicts a High Risk of Acute Leukemic Transformation in Primary Myelodysplastic Syndrome.
Authors: Wu Shang-Ju , Chou Wen-Chien , Yao Ming , Yeh Yo-Chia , Tien Hwei-Fang 
Published: October 2019

Abstract
The suppressor of cytokine signaling-1 (SOCS1) protein is a tumor suppressor. Hypermethylation of SOCS1, resulting in transcriptional silencing, is suggested to play an important role in the development of cancers. We sought to characterize SOCS1 methylation in primary myelodysplastic syndrome (MDS) and to clarify its clinical implications. We analyzed the methylation status of SOCS1 by methylation specific polymerase chain reaction in 114 patients with primary MDS and performed serial studies in 29 of them. SOCS1 methylation occurred in 54 patients (47.4%), more frequently in patients with high-risk subtypes of MDS than in those with low-risk ones (52.6% vs. 25.8%, p = 0.011). SOCS1 methylation was closely associated with N-RAS gene mutation (p = 0.010) and inversely associated with good-risk karyotype (p = 0.021). With a median follow-up of 17 months (range, 1 to 231 months), two patients, who did not have SOCS1 methylation at diagnosis, acquired it during disease progression. SOCS1 methylation disappeared after hematopoietic stem cell transplantation in two patients who had it initially. The patients with SOCS1 methylation had a higher cumulative risk of leukemic transformation than the others (55.8% vs. 27.7% at 3 years, p = 0.004). This difference remained significant within the subgroup of patients with high-risk subtypes of 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.
Correlation of SOCS1 methylation with clinical characteristics, cytogenetics and RAS mutations Total(n=114) SOCS1 methylated(n=54) SOCS1 unmethylated(n=60) p value Age 64(7~68) 64(7~84) 65(19~86) 0.231 Sex(M/F) 81/33 36/18 45/15 0.327 WBC(1000/ml) 4675(220~227200) 4710(440~227200) 4640(1570~87420) 0.913 Hemoglobin(g/dl) 8.5(3.9~14.4) 8.9(4.4~12.9) 7.8(3.9~14.4) 0.348 Platelet(1000/ml) 88.5(2~607) 102(2~400) 74(3~607) 0.453 BM blast(%) 5.8(0~54.8) 7.2(0~54.8) 4.4(0~25.4) 0.033 Cytogenetics 0.021 Poor 19 13(68.4%) 6(31.6%)     -7/7q- 11 8(72.7%) 3(27.3%)     complex 10 6(60%) 4(40%) Intermediate 15 10(66.7%) 5(33.3%) Good 70 27(38.6%) 43(61.4%) FAB subtypes 0.011 Low-risk 31 8(25.2%) 23(74.2%)     RA 21 4(19.0%) 17(81.0)     RARS 10 4(40%) 6(60%) High-Risk 78 41(52.6%) 37(47.4%)     RAEB 33 20(60.6%) 13(39.4%)     RAEB-T 20 11(55.0%) 9(45.0%)     CMML 25 10(40.0%) 15(60.0%) AML 5 5(100%) 0 IPSS 0.008 Low-risk 57 21(36.8%) 36(63.2%)     Low 21 4(19.0%) 17(81.0%)     Int-1 10 4(40.0%) 6(60.0%) High-risk 46 29(63.0%) 17(37.0%)     Int-2 33 29(63.0%) 17(37.0%)     High 20 11(55.0%) 9(45.0%) N-RAS 0.010     Mutated 11 9(81.8%) 2(18.2%)     Wild 96 38(39.6%) 58(60.4%) K-RAS 1.000     Mutated 4 2(50%) 2(50%)     Wild 101 44(43.6%) 57(56.4%)
Cumulative risk of leukemic transformation in MDS patients. A. Comparison for all patients with and without SOCS1 methylation. B. Comparison for patients of high-risk subtypes of MDS (RAEB, RAEB-T, CMML) with and without SOCS1 methylation Cumulative risk of leukemic transformation in MDS patients. A. Comparison for all patients with and without SOCS1 methylation. B. Comparison for patients of high-risk subtypes of MDS (RAEB, RAEB-T, CMML) with and without SOCS1 methylation