System of Markers Based on the Methylation of a Group of Proapoptotic Genes in Combination with MicroRNA in the Diagnosis of Breast Cancer

E A Braga; A M Burdennyy; I V Pronina; E A Filippova; T P Kazubskaya; M V Fridman; D S Khodyrev; A V Karpukhin; V I Loginov; N E Kushlinskii

doi:10.1007/s10517-020-04710-2

System of Markers Based on the Methylation of a Group of Proapoptotic Genes in Combination with MicroRNA in the Diagnosis of Breast Cancer

Bull Exp Biol Med. 2020 Jan;168(3):366-370. doi: 10.1007/s10517-020-04710-2. Epub 2020 Jan 15.

Authors

E A Braga^{1

2}, A M Burdennyy^{3

4}, I V Pronina³, E A Filippova³, T P Kazubskaya⁵, M V Fridman⁶, D S Khodyrev⁷, A V Karpukhin⁸, V I Loginov^{3

8}, N E Kushlinskii⁵

Affiliations

¹ Research Institute of General Pathology and Pathophysiology, Moscow, Russia. eleonora10_45@mail.ru.
² N. P. Bochkov Research Center of Medical Genetics, Moscow, Russia. eleonora10_45@mail.ru.
³ Research Institute of General Pathology and Pathophysiology, Moscow, Russia.
⁴ N. M. Emanuel Institute for Biochemical Physics, Russian Academy of Sciences, Moscow, Russia.
⁵ N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia.
⁶ N. I. Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.
⁷ Federal Research Clinical Center of Specialized Types of Medical Care and Medical Technologies of Federal Medical-Biological Agency of Russia, Moscow, Russia.
⁸ N. P. Bochkov Research Center of Medical Genetics, Moscow, Russia.

PMID: 31938917
DOI: 10.1007/s10517-020-04710-2

Abstract

Systems of markers for the diagnosis of breast cancer based on DNA methylation of a group of suppressor protein-coding genes, hypermethylated microRNA genes, and their combinations were compiled. On a representative sample of 70 paired breast cancer specimens (tumor/normal), MS-PCR analysis revealed a significant increase in the methylation frequency of 5 protein-coding genes: RASSF1A suppressor and apoptosis genes APAF1, BAX, BIM/BCL2L11, and DAPK1 (34-61% vs. 4-24%) and 6 microRNA genes: MIRG124G1, MIRG125bG1, MIRG129G2, MIRG148a, MIRG34b/c, and MIRG9G3 (36-76% vs. 6-27%). ROC-analysis showed that a combination of 4 genes (APAF1, BAX, BIM/BCL2L11, and DAPK1) and MIRG125bG1 gene constitute a highly efficient 5-marker system with 100% specificity and sensitivity of 94-96% at AUC=0.98-0.97, suitable also for patients with stage I and II breast cancer. Detection of methylation of at least one gene in this system in biopsy or postoperative material is sufficient to refer the sample to breast cancer.

Keywords: breast cancer; diagnostic marker systems; methylation; microRNAs; proapoptotic genes.

MeSH terms

Apoptotic Protease-Activating Factor 1 / genetics
Bcl-2-Like Protein 11 / genetics
Breast Neoplasms / diagnosis*
Breast Neoplasms / genetics*
DNA Methylation / genetics
DNA Methylation / physiology
Death-Associated Protein Kinases / genetics
Female
Gene Expression Regulation, Neoplastic / genetics
Humans
In Vitro Techniques
Mass Spectrometry
MicroRNAs / metabolism*
Polymerase Chain Reaction
Tumor Suppressor Proteins / genetics

Substances

APAF1 protein, human
Apoptotic Protease-Activating Factor 1
BCL2L11 protein, human
Bcl-2-Like Protein 11
MicroRNAs
RASSF1 protein, human
Tumor Suppressor Proteins
DAPK1 protein, human
Death-Associated Protein Kinases