Evaluation of abnormal promoter DNA hypermethylation of the integrin, nidogen, and dystroglycan genes in breast cancer
The RCMG Epigenetics Laboratory researchers studied a number of genes to find out whether their methylation be one of the main causes of carcinogenesis.
“In tumors, the genome and epigenome are unbalanced and a huge number of new mutations arise. A gene that is unmethylated in normal tissue but methylated in tumors is usually considered the gene that "turns off" and "triggers carcinogenesis”, explained Dr. Vladimir Strelnikov, Head of the RCMG Epigenetics Laboratory. “There is a concept of driver and passenger mutations. The first ones trigger the process of tumor development, and the second ones are not directly associated with etiopathogenesis. We think that passenger methylation also exists - it won't tell the doctor anything. It is extremely important to know about the passenger methylation so that you don't make any mistakes.”
“For example, if abnormal methylation of several genes is found in a tumor, and a panel for clinical use is made based on that alone, it may be erroneous because the methylation of those genes in the tumor is not actually related to the disease development.”
The RCMG researchers drew attention to the ITGA4 gene. It is "silent" both in healthy tissues and in most tumors, but according to statistics, its methylation in tumors is not just a passenger event. It turns out that the gene is hypermethylated in tumors of one molecular subtype of breast cancer - HER2 positive. This subtype of cancer is considered aggressive, and its main molecular event is abnormal activity of the HER2 gene, the product of which is the corresponding protein; it subsequently forms a receptor on the surface of tumor cells. Product of the ITGA4 gene is also a surface receptor protein. Both of them transmit signals inside the tumor cell and regulate the cell cycle. The fact that the ITGA4 gene is methylated in HER2 positive tumors suggests that the regulatory pathways of the two receptors are similar. The researchers suggest that HER2 positive tumors "do not benefit" from having the ITGA4 gene expressed, i.e. working. However, in such tumors, only one copy of the ITGA4 gene is "silent," and for the gene to be completely "turned off," both copies must be methylated.
“We assume that the HER2 gene has no "desire" to completely destroy ITGA4, it only benefits from reducing its activity so that the corresponding protein help in cell cycle regulation. When we study signals going inside the cell from HER2 and ITGA4 receptors we might find additional means for HER2 positive cancer treatment”, Vladimir Strelnikov assures. “Today Herceptin is prescribed for this cancer subtype, but it is not efficient in all cases. Assessment of the ITGA4 gene condition can be a diagnostic sign that will show how effective Herceptin treatment will be in each particular case. Secondly, we cannot rule out the possibility that by targeting the ITGA4 receptor signaling pathway we can increase the effectiveness of therapy with existing drugs, enhancing their effect in those cells that respond poorly to it.”
Russian Science Foundation grant No.18-15-00430, "DNA Methylation in Assessment of Response to Neoadjuvant Chemotherapy in Breast Cancer" supported the research.
Strelnikov, V.V., Kuznetsova, E.B., Tanas, A.S. et al. Abnormal promoter DNA hypermethylation of the integrin, nidogen, and dystroglycan genes in breast cancer. Sci Rep 11, 2264 (2021).