23 October 2012

A new epigenetic marker of breast cancer

Breast cancer: genetics suggests, and epigenetics disposes

Ilya Shcheglov, "Science and Life"

A new epigenetic marker of breast cancer has been found. Scientists analyzed 450 thousand methylation sites throughout the genome of 36 pairs of identical twins with discordance for this disease.

It's no secret that genetic mutations play a huge role in the development of certain forms of cancer. Many of these mutations and the risk of neoplasia associated with them are described. However, despite the critical importance of the "genetic basis", epigenetic processes can play an equally significant role in the development of these pathologies.

Epigenetic changes do not disrupt the sequence of nucleotides in DNA and are not inherited, but due to chemical modification of certain chromosomal loci and associated genes, they critically change their availability for the transcription apparatus of the cell. (Examples of epigenetic changes are acetylation and methylation of histones, DNA methylation.) Such epigenetic "on/off" of genes, in particular, underlies the differentiation – acquisition of the necessary phenotype – of all types of somatic cells. Conversely, a change in the characteristic "epigenetic labeling" of a cell of one type or another leads to de-differentiation or a change of phenotype (trans-differentiation) into another cell type, for example, from the epithelium to the mesenchyma. Given such a scale of the effects of epigenetic regulation, it is not difficult to understand that violations of this process can lead to the development of pathologies, such as carcinogenesis.

DNA methylation, as one of the most important mechanisms of epigenetic regulation, was discovered at the turn of the eighties of the last century. The essence of this process is the conversion of the cytosine nucleotide residue into 5-methylcytosine. For a long time it was believed that the only functional consequence of methylation is transcriptional repression of genes, since the "islands" of methylation, most often found in the promoter sequences of genes, conformationally prevent the interaction of this DNA site with protein transcription factors necessary for the expression of this gene. However, it later turned out that in some cases this process can also mediate the activation of gene expression. But, one way or another, the correct methylation pattern is critically necessary for normal cellular differentiation and development of the organism.

In the course of neoplastic degeneration, the picture of epigenetic modification, as a rule, changes in such a way that the overall level of genome methylation is significantly reduced, while regulatory regions of a significantly smaller part of genes (most often, oncosuppressor genes), on the contrary, are hypermethylated and suppressed. Accordingly, if a change in normal methylation in any of the genes plays an important role in the development of a certain form of cancer, then the establishment of such a phenomenon will contribute not only to a better understanding of the pathogenesis of this disease, but may also turn out to be a kind of epigenetic marker of this disease.

One of these previously unknown specific epigenetic markers of breast cancer, namely hypermethylation of the promoter region of the DOK7 gene, was discovered by an international group of scientists who recently published the results of their work in the journal Carcinogenesis (Heyn et al., DNA methylation profiling in breast cancer discordant identical twins identifies DOK7 as novel epigenetic biomarker).

Breast cancer (breast cancer) is the most common form of neoplasia in women (approximately one case per nine women). At the same time, only in 30% of cases it is inherited. In other words, in absolutely most cases, sporadic mutations and epigenetic changes become the cause of this disease. Among the latter, hypermethylation and, as a consequence, "silencing" of the BRCA1 and BRCA2 genes, known oncosuppressors involved in homologous recombination during DNA damage repair, is most often noted. The discovery of these epigenetic markers allowed, at one time, to establish that their carriers respond much better to treatment with such chemotherapeutic agents as PARP inhibitors and cisplatin than other patients diagnosed with breast cancer. Accordingly, the establishment of epigenetic markers occurring in this disease with a lower frequency could also help in the development of other personalized treatment methods.

For this purpose, the authors applied a newly developed method for comparing methylation patterns in identical twins, successfully applied in similar studies of type I diabetes mellitus and systemic lupus erythematosus.

Identical twins are genetically identical, but during embryogenesis and subsequent postnatal development, a number of phenotypic differences arise between them, a phenomenon known as "discordance of identical twins". One of the manifestations of discordance, mostly determined by epigenetic changes, may be the development of a disease in one of the twins in the absence of this disease in the other. In this case, a comparison of the epigenetic maps of two twins can detect epigenetic markers of this disease.

In their study, the authors used peripheral blood cells and compared 450 thousand methylation sites throughout the genome of 36 pairs of identical twins with breast cancer discordance. A total of 403 genome regions with different methylation were detected. As expected, the vast majority of them were associated with hypomethylation of the genome, characteristic of cancer. Of the remaining part, more attention was paid to hypermethylated regions of the regulatory sequences of 14 genes that showed the greatest differences in methylation. Most of these genes turned out to be already known participants in the pathogenesis of breast cancer and other cancers. However, the carcinogenic functions of one of them, DOK7 (or rather, one of its isoforms transcribed from an alternative promoter), which showed just the most significant differences in methylation, turned out to be practically unknown.

Verification of the possibility of using DOK7 as an epigenetic marker of breast cancer, carried out on postoperative breast cancer samples and breast cancer cell culture lines, fully confirmed the correlation found. Moreover, the analysis showed that DOK7, as a marker, has unique prognostic characteristics. Namely, hypermethylation of one of its promoters in peripheral blood cells can be detected several years before the diagnosis of breast cancer itself.

Further research in this area, according to scientists, will be related to the clarification of the exact functions of DOK7, namely, its isoform, which is synthesized from the promoter hypermethylated in breast cancer in normal and carcinogenesis.

Portal "Eternal youth" http://vechnayamolodost.ru23.10.2012

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