Роль метилирования генов системы апоптоза в патогенезе рака молочной железы и яичников

E. A. Filippova; A. M. Burdennyy; S. S. Lukina; I. V. Pronina; T. P. Kazubskaya; E. A. Braga; V. I. Loginov

doi:10.25557/2310-0435.2021.03.55-61

E. A. Filippova Institute of General Pathology and Pathophysiology, Moscow, Russia http://orcid.org/0000-0001-7172-0433
A. M. Burdennyy Institute of General Pathology and Pathophysiology, Moscow, Russia http://orcid.org/0000-0002-9398-8075
S. S. Lukina Institute of General Pathology and Pathophysiology, Moscow, Russia http://orcid.org/0000-0001-6246-2444
I. V. Pronina Institute of General Pathology and Pathophysiology, Moscow, Russia http://orcid.org/0000-0002-0423-7801
T. P. Kazubskaya N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia http://orcid.org/0000-0001-5856-0017
E. A. Braga Institute of General Pathology and Pathophysiology, Moscow, Russia http://orcid.org/0000-0001-5188-4094
V. I. Loginov Institute of General Pathology and Pathophysiology, Moscow, Russia http://orcid.org/0000-0003-2668-8096

DOI: https://doi.org/10.25557/2310-0435.2021.03.55-61

Keywords: methylation, apoptosis, breast cancer, ovarian cancer

Abstract

Background. Breast cancer (BC) and ovarian cancer (OC) are the most commonly diagnosed types of cancer in women, which are characterized by severe course and unfavorable prognosis. In Russia, more than 29,000 people die from these types of tumors every year. Aberrant methylation of CpG islands located in the promoter regions of apoptosis genes play an important role in the pathogenesis of this disease. Previously, there were reports of hypermethylation of the DAPK1, APAF1, BCL2, and TP53 genes in some types of tumors.
However, reports of the role of the gene methylation in the progression of BC and OC are scarce, and for the BIM and BAX genes, this information is absent. The aim of this study was to elucidate the role of methylation for six genes of the apoptosis system, namely, the pro-apoptotic genes APAF1, DAPK1, BIM, BAX, TP53, as well as the anti-apoptotic gene BCL2, in the progression of BC and OC.

Methods. Samples of breast and ovarian tumors were collected and clinically characterized at the N.N. Blokhin Research Institute of Clinical Oncology. High molecular weight DNA was isolated from the tissue using standard methods. The methylation degree was assessed by bisulfite DNA conversion and real-time quantitative methylation-specific PCR (MS-PCR). Significance of differences between the study groups was determined with the nonparametric Mann-Whitney test for independent samples.
Results. The degree of BCL2, DAPK1, and BAX gene methylation was significantly increased (p<0.05) in tumor samples compared to matched histologically normal ovarian tissue. Hypermethylation of four pro-apoptotic genes (DAPK1, APAF1, BIM, and BAX) and, in contrast, hypomethylation of BCL2 were observed in BC. In addition, in BC, the promoter CpG island methylation of DAPK1, BIM, BAX, APAF1 genes significantly correlated with the clinical stage (p < 0.001), and with the tumor size (p < 0.02) whereas for BIM and BAX genes, the methylation degree correlated with metastasis (p < 0.02). In OC, the methylation degree of the BAX gene significantly correlated with the clinical stage, with the tumor size, and with metastasis (p < 0.05).
Conclusion. The results of this study showed the role of apoptosis gene methylation in the development and progression of BC and OC and also allowed evaluating their influence on the pathophysiological profile of ovarian and breast tumors.

The role of apoptosis gene methylation in the pathogenesis of breast and ovarian cancer

Abstract