Researchers describe DNA methylation changes in bone cancer

Study indicates that chemical signaling affects gene regulation and is linked to the development of osteosarcoma

Tumors are not only caused by genetic mutations. In childhood bone cancer, also known as osteosarcoma, changes in methyls—chemical tags attached to DNA that help regulate genes—also contribute to tumor development. The changes deregulate a series of genes, leading to accelerated cell multiplication, according to an article published in the journal Molecular Genetics and Genomics.

“We found two patterns in different parts of the genome, one where methylation was higher than expected and the other where it was lower,” says biomedical researcher Mariana Maschietto of the Boldrini Center in Campinas, who led the study. Through different mechanisms, the two modifications resulted in accelerated tumor growth.

Methylation is a type of epigenetic modification of the genome, through which gene activity is altered without changing the letters of the DNA. According to Maschietto, it causes cells to turn genes on or off according to their needs.

This is especially important during fetal development when cell differentiation is occurring, as well as during the teenage years. It also allows adult cells to adapt to changes in the environment. “The genes themselves do not have this plasticity,” explains the researcher.

According to the data from the article, excessive methylation was seen in the regulatory regions of certain genes that contribute to bone formation. The activity of these genes thus decreased, causing tumors to grow faster.

Another affected gene helps correct DNA duplication failures that occur during cell division. When methylation is higher than normal, fewer duplication errors are eliminated and a greater number of mutations appear in the genome. Some of these changes can contribute to cancer and accelerate its growth.

“Excess methylation is related to increased activity of the DNMT3B gene,” says Maschietto. This gene produces an enzyme that generally appears in greater quantities in osteosarcoma and is responsible for methylation in the regulatory regions of these genes.

Diffuse pattern

The researchers noticed that a second modified methylation pattern—in this case, with fewer tags than normal—occurred throughout the genome.

“When this dispersed signaling decreases globally, the genome, which is normally compact, unravels, facilitating the expression of genes that accelerate the cell cycle,” explains Mariana Brait, a researcher at Johns Hopkins University and senior research manager at the A.C.Camargo Cancer Center, who works on cancer methylation and was not involved in the study.

“In practice, this accelerates cell division and tumor growth and makes the genome unstable,” adds Maschietto. This happens because it decreases the activity of another gene, called TET1, which triggers a chain of reactions that lead to the suspension of methylation in these DNA stretches.

“The study reveals new and important data that can help us to understand osteosarcoma,” says Sheila Coelho, a biologist from Brazil’s National Cancer Institute (INCA) who was not involved in the study.

According to the scientist, one of the strengths of the research was that it compared osteosarcoma tissues with tissue from patients without the disease.

“It is very difficult to obtain bone tissue from normal patients, so tissue from patients with other types of cancer was used,” explains Coelho. The samples were extracted via biopsies conducted to check whether the bones were affected.

Coelho highlights one limitation of the study: it did not look at the APOBEC gene, which can also cause genome instability, repair errors, and an accumulation of mutations in the event of excessive methylation in the regulatory region.

Epigenetics and development

In adults, mutations accumulate over decades of exposure to carcinogenic factors that alter DNA, but children and adolescents are predominantly affected by epigenetic mechanisms. “Unlike gene mutations, which are unalterable once they occur, epigenetic flaws can be reversible. They can adapt to a stimulus before going back to normal when it disappears,” explains Brait.

“Epigenetics is the main approach being used to develop childhood cancer treatments and diagnoses,” says Maschietto. Many pediatric tumors are already classified based on methylation patterns, particularly at specialist cancer centers.

This approach makes it possible to identify previously undiagnosed tumors. “Knowledge of these mechanisms also serves as a basis for developing new drugs that act on methylation,” adds Maschietto.

“Drugs of this type are already used for blood cancers,” notes Brait. But these drugs still do not work as well against solid tumors.

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