Clinical significance of methylation of lncRNA genes GAS5, ZEB1-AS1 in tumors of patients with breast cancer

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Introduction. Long non-coding RNAs (LncRNAs) are transcripts whose role in carcinogenesis is poorly understood. LncRNA expression determines the biological properties of a cell, including invasive potential and ability to migrate. Methylation status changes lncRNA functions and can be a marker of tumor prognosis.

The aim of the work is study the methylation frequency of the LncRNA genes GAS5, ZEB1-AS1 in breast cancer and to evaluate the clinical significance.

Material and methods. 140 patients with breast cancer were examined, mainly with T1 – (38.7%) and T2 – (55.6%) stages, N0 status – (54.0%), N1 status – (37.9%). Luminal type of breast cancer – 80% (n = 113), non-luminal – 20% (n = 27). Morphologically: invasive ductal carcinoma (77.1%), G2 differentiation (62.9%) were predominantly detected. Methylation of CpG regions of promoter regions of the GAS5, ZEB1-AS1 lncRNAs genes in paired tumor and histologically unaffected breast tissue samples was studied using the methyl-specific PCR method. The T100 amplifier (Bio-Rad, USA) and Lasergene 17.1 primers from DNASTAR (USA) were used in the work. Statistical data processing was performed in the SPSS, v. 23 program.

Results. The frequency of methylation of the GAS5, ZEB1-AS1 genes in the tumor is higher than in histologically unaffected breast tissue. Gene methylation is associated with age, R = 0.43 (GAS5) and R = 0.26 (ZEB1-AS1), and increases the stage tumor process. A correlation was established between GAS5 gene methylation and the T index (R = 0.21, p < 0.05), N status (R = 0.31, p < 0.05). There is an inverse correlation with the biological subtype of luminal cancer (R = –0.29, p < 0.05). The absence of methylation of the GAS5 and ZEB1-AS1 genes is associated with a decrease in 5-year overall survival and 10-year progression-free survival in breast cancer.

Conclusions. In breast cancer, methylation of the lncRNAs GAS5, ZEB1-AS1 genes in the tumor exceeds that in the unchanged breast tissue. The methylation status of the genes GAS5, ZEB1-AS1 is associated with the stage, tumor size, regional metastasis, and does not affect the long-term treatment results.

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作者简介

A. Osipova

Russian University of Medicine Ministry of Health of Russia

编辑信件的主要联系方式.
Email: osipova_ronc@mail.ru
ORCID iD: 0009-0003-3046-9117
SPIN 代码: 1068-1015

Post-graduate Student, Department of Oncology

俄罗斯联邦, 4 Dolgorukovskaya, Moscow, 127006

D. Ryabchikov

N.N. Blokhin National Medical Research Center of Oncology Ministry of Health of Russian Federation

Email: dr.denisr@mail.ru
ORCID iD: 0000-0003-2670-2361
SPIN 代码: 9328-9425

Dr.Sc. (Med.), Head of the Department of Abdominal Oncology

俄罗斯联邦, 24 Kashirskoe shosse, Moscow, 115522

S. Chulkova

N.N. Blokhin National Medical Research Center of Oncology Ministry of Health of Russian Federation; I.I. Pirogov Russian Research Medical University

Email: chulkova@mail.ru
ORCID iD: 0000-0003-4412-5019
SPIN 代码: 1676-2156

Dr.Sc. (Med.), Senior Research Scientist, Laboratory of Clinical Immunology and Innovative Technologies, Assistant Professor, Department of Oncology and Radiotherapy

俄罗斯联邦, 24 Kashirskoe shosse, Moscow, 115522; 1a Ostrovityanova, Moscow, 117997

V. Loginov

Research Institute of General Pathology and Pathophysiology

Email: loginov7w@gmail.com
ORCID iD: 0000-0003-2668-8096
SPIN 代码: 6249-5883

Ph.D. (Biol.), Leading Research Scientist, Laboratory of Pathogenomics and Transcriptomics

俄罗斯联邦, 8 Baltiyskaya, Moscow, 125315

A. Burdennyy

Research Institute of General Pathology and Pathophysiology

Email: burdennyy@gmail.com
ORCID iD: 0000-0002-9398-8075
SPIN 代码: 4429-4288

Ph.D. (Biol.), Leading Research Scientist, Laboratory of Pathogenomics and Transcriptomics

俄罗斯联邦, 8 Baltiyskaya, Moscow, 125315

N. Kushlinskii

Russian University of Medicine Ministry of Health of Russia; N.N. Blokhin National Medical Research Center of Oncology Ministry of Health of Russian Federation

Email: biochimia@yandex.ru
ORCID iD: 0000-0002-3898-4127
SPIN 代码: 6225-1487

Dr.Sc. (Med.), Professor, Member of RAS, Head of the Department of Clinical Biochemistry, Scientific Head of Clinical Diagnostic Laboratory

俄罗斯联邦, 4 Dolgorukovskaya, Moscow, 127006; 24 Kashirskoe shosse, Moscow, 115522

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2. Fig. 1. Methylation rates of the GAS5, ZEB1-AS1 genes in tumor tissue in different molecular biological types of breast cancer, taking into account the stage of the disease

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3. Fig. 2. Survival graphs of breast cancer patients based on the methylation status of the GAS5 gene in tumor tissue: left – overall survival; right – progression-free survival

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4. Fig. 3. Survival graphs of breast cancer patients based on the methylation status of the ZEB1-AS1 gene in tumor tissue: left – overall survival; right – progression-free survival

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