The "cold spots" mutations in the cancer genome

Mutations are changes to DNA that occur gradually in human cells as they replicate and the organism grows and ages.

Some of these changes, especially when they occur in genes, may be critical during cancer development. Therefore, it is important to differentiate changes that have the potential to be relevant to the disease from others that will accumulate without consequences.

Understanding and characterizing harmless changes is a fundamental methodology for detecting other changes that differ from them and can lead to better identification of those that are harmful.

In a new study, ICREA researcher Dr. Fran Supek and Dr. David Mas Ponte, both from the Barcelona Institute for Research in Biomedicine (IRB Barcelona), have discovered variations in small-scale mutation rates within genes.

Through this study, they have identified “cold spots,” in which the mutation load is lower than usual, and have linked them to low DNA methylation, a common epigenetic mark, establishing a direct mechanism linked to its regulation.

“Understanding the distribution of mutation rates could facilitate the development of targeted therapies to protect specific genomic regions or diagnostic tools to monitor these regions. These therapies could contribute to the prevention of the accumulation of mutations that drive the development or progression of the disease. cancer,” explains Dr. Supek.

These discoveries arose from analysis of data on mutations found in cancer cells and healthy tissues, along with DNA methylation and other epigenetic data sets.

Certain mutations in DNA can promote cancer. In the image, cancer cells and DNA chain. (Illustration: Amazings/NCYT)

Mutations and epigenetics

Epigenetics encompasses chemical modifications to both DNA and the proteins that cover it, such as histones, and regulates gene expression without changing the DNA sequence.

DNA methylation is a natural process that can influence the activity of a gene. It is one of the most common epigenetic alterations and is especially important for active genes, since they are normally expressed in tumors.

Unlike other histone modifications, which occur over large sections of genes, DNA methylation patterns vary over short gene segments and are therefore also relevant in quantifying rate variability. of mutation throughout the genome and adjacent regulatory regions.

“Through this study we can better understand the factors that contribute to the unequal distribution of mutations within genes, which provides us with valuable information about the mechanisms of mutagenesis and cancer evolution,” concludes Dr. Supek.

The study is titled “Mutation rate heterogeneity at the sub-gene scale due to local DNA hypomethylation.” And it has been published in the academic journal Nucleic Acids Research. (Source: IRB Barcelona)