Epigenetic and genetic investigation of SOCS-1 gene in patients with multiple myeloma

Fatıma Ceren Tuncel; Istemi Serin; Sacide Pehlivan; Yasemin Oyaci; Mustafa Pehlivan

doi:10.5045/br.2022.2022097

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Original Article

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Blood Res 2022; 57(4):

Published online December 31, 2022

https://doi.org/10.5045/br.2022.2022097

Epigenetic and genetic investigation of SOCS-1 gene in patients with multiple myeloma

Fatıma Ceren Tuncel¹, Istemi Serin², Sacide Pehlivan¹, Yasemin Oyaci¹, Mustafa Pehlivan³

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¹Department of Medical Biology, Faculty of Medicine, Institute of Health Sciences, Istanbul University, ²Department of Hematology, Istanbul Training and Research Hospital, University of Health Sciences, Istanbul, ³Department of Hematology, Faculty of Medicine, Gaziantep University, Gaziantep, Turkey

Correspondence to : Istemi Serin, M.D.
Department of Hematology, Istanbul Training and Research Hospital, University of Health Sciences, Org. Nafiz Gurman Cad. Fatih 34098, Istanbul, Turkey
E-mail: serinistemi@hotmail.com

Received: May 11, 2022; Revised: August 17, 2022; Accepted: September 8, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Background
The suppressor of cytokine signaling-1 (SOCS-1) functions to induce an appropriate immune response and is an essential physiological regulator of interferon signaling. DNA methylation involves adding a methyl group to the carbon 5 position of cytosine. Besides comparing SOCS-1 gene methylation status between patients with multiple myeloma (MM) and healthy controls, this study also aimed to demonstrate the effect of SOCS-1 gene distribution and the effect of methylation of SOCS-1 on progression-free survival (PFS) and overall survival (OS).
Methods
This study included 120 patients diagnosed with MM between January 2018 and 2020 and 80 healthy individuals. The distribution of the SOCS-1 genotypes was statistically compared between MM patients and healthy controls. Additionally, the statistically significant effects of these genotypes on survival were examined.
Results
The CA/CA genotype of SOCS-1 was significantly higher in healthy controls (P=0.001), while the Del/Del genotype was significantly higher in patients with MM (P=0.034). The percent methylated reference (PMR) value of the SOCS-1 gene was significantly higher in the healthy controls (median, 43.48; range, 2.76‒247.75; P=0.001). Patients with a PMR value of ≥43.48 were 3.125 times more likely to develop progression than those with a PMR value of ＜43.48.
Conclusion
The effects of SOCS-1 polymorphisms on the pathogenesis of MM and SOCS-1 methylation will further shed light on the pathophysiology of MM.

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Keywords: Multiple myeloma, SOCS-1, Epigenetics, Methylation, Survival

Article

Original Article

Blood Res 2022; 57(4): 250-255

Published online December 31, 2022 https://doi.org/10.5045/br.2022.2022097

Epigenetic and genetic investigation of SOCS-1 gene in patients with multiple myeloma

Fatıma Ceren Tuncel¹, Istemi Serin², Sacide Pehlivan¹, Yasemin Oyaci¹, Mustafa Pehlivan³

Correspondence to:Istemi Serin, M.D.
Department of Hematology, Istanbul Training and Research Hospital, University of Health Sciences, Org. Nafiz Gurman Cad. Fatih 34098, Istanbul, Turkey
E-mail: serinistemi@hotmail.com

Received: May 11, 2022; Revised: August 17, 2022; Accepted: September 8, 2022

Abstract

Keywords: Multiple myeloma, SOCS-1, Epigenetics, Methylation, Survival

Abstract

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Figure 1.Progression-free survival (PFS) analysis between patients’ subgroups in terms of SOCS-1 gene methylation status.

Blood Research 2022; 57: 250-255https://doi.org/10.5045/br.2022.2022097

Table 1 . Clinical features and treatment regimens of patients with MM..

	Multiple myeloma
	Median	N=120 (%)
Age	55 (32–70)
Gender
Female/male		56/64 (47/53)
Stage (Durie-Salmon)
II/III		29/69 (37.9/62.1)
ISS
I		31 (32)
II/III		25/41 (25.8/41.3)
Hemoglobin
gr/dL	10.3 (6.2–15)
Leukocyte
/mL	6,900 (2,760–18,500)
Platelets
/mL	183,000 (103,000–406,000)
C-reactive protein	7.2 (2.1–352)
mg/dL
LDH
IU/L	203 (93–1,037)
B2-microglobulin
mg/L	5 (1.5-47.4)
Albumin
gr/L	3.5 (1.6–5.1)
Treatment
VCD, ASCT, LD (%)	(100)
OS (5-year, %)	(80)
PFS (5-year, %)	(52)
Relapse		44 (36.7)
Mortality		18 (15)
Follow-up duration (mo)	38.3 (4.1–105.3)

Abbreviations: ASCT, autologous stem cell transplantation; IPI, International prognostic index; LD, lenalidomide, dexamethasone; LDH, lactate dehydrogenase; OS, overall survival; PFS, progression-free survival; VCD, bortezomib, cyclophosphamide, and dexamethasone..

Table 2 . Comparison of frequencies of SOCS-1 gene rs33989964 variants between patients with multiple myeloma and healthy controls..

SOCS-1	Genotype	Multiple myeloma N=120 (%)	Healthy control N=80 (%)	OR Exp(B)	95% CI	P
SOCS-1	CA/CA	20 (16.7)	30 (37.5)	0.243^a)	0.106–0.558^a)	0.001^a)
	CA/Del	49 (40.8)	29 (36.3)	0.620^a)	0.294–1.309^a)	0.210^a)
	Del/Del	51 (42.5)	21 (26.2)	0.498^b)	0.269–0.923^b)	0.034^b)
Allele
	CA	89 (37.1)	89 (55.6)
	Del	151 (62.9)	71 (44.4)	2.127^b)	1.415–3.196^b)	0.001^b)
2^-ΔΔCt	×100 (PMR)	20.11 (2.11–717.30)	43.48 (2.76–247.75)			0.001^c)

^a)OR (95% CI) was adjusted by age and sex, ^b)Fisher’s Exact test, ^c)Median test..

Table 3 . Comparison of PFS and OS with prognostic factors of patients with MM..

	N	PFS (5-year %)	Log-rank P-value	OS (5-year %)	Log-rank P-value
Gender	120	52		80
Female/male	56/64	61/40	0.121	94/69	0.005
Age
<65/≥65	103/17	55/24	0.281	86/34	0.001
ISS
I	31	61		92
II	25	57		78
III	41	40	0.632	62	0.008
ISS
I–II	56	59		90
III	41	40	0.363	63/62	0.002
ECOG
≤1/>1	113/7	52/42	0.951	81/50	0.668
LDH (IU/L)
<480/≥480	92/5	53/40	0.272	80/60	0.216
CRP (mg/L)
<5/≥5	44/53	59/44	0.217	91/67	0.015
SOCS-1 (rs33989964) genotypes
CA/CA	20	27		81
CA/Del	49	63		80
Del/Del	51	52	0.229	78	0.763
SOCS-1 (rs33989964)
CA/CA	20	27		81
CA/Del+Del/Del	100	57	0.140	79	0.462
2^-ΔΔCt×100 (PMR)
<43.48	84	56		82
≥43.48	36	43	0.027	77	0.484

Abbreviations: CRP, C-reactive protein; ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; LDH, lactate dehydrogenase; OS, overall survival; PFS, progression-free survival; PMR, percent methylated reference; SOCS-1, suppressor of cytokine signaling-1..

Table 4 . Statistical analysis according to the PMR cut-off value of 43.48..