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Augusts 2, 2024According to research by IRB Barcelona, when the gene is mutated and has an altered number of copies, it is more likely to contribute to the development of cancer.
Cancer is caused by genetic changes that occur in our cells over time. There are two main types of alterations: somatic mutations, which are changes in the DNA sequence, and variations in the number of copies of a gene in particular. It was known that these two types of alterations interact to promote cancer, but systematic studies detailing the mechanism of action were lacking.
«Cancer progression is significantly influenced by the interaction between alterations in gene copy number and mutations»
IRB Barcelona scientists
Now, scientists from IRB Barcelona have published new findings in Nature Communications., revealing that cancer progression is significantly influenced by the interaction between gene copy number alterations and mutations.
The research confirms previous studies that suggested that a decrease in copy number correlates with mutations in tumor suppressor genes (hindering their protective functions against cancer), while an increase in copy number correlates with a greater number of mutations in oncogenes that drive cancer development.
Unexpectedly, researchers have also established a link between an increase in gene copy number and mutations in tumor suppressor genes, and a link between lower copy number and more mutations in various oncogenes. The scientific team observed that both paradoxical associations between mutations and copy number are frequent in cancer genomes.
Los investigadores Elizaveta Besedina y Fran Supek have provided new knowledge about the role of genetic alterations in cancer development, opening new avenues to consider tumor suppressor genes as possible targets for cancer treatment.
“Our research reveals that both increases and decreases in gene copy number can occur in surprising ways, driving cancer evolution,” explains Supek, head of the Genome Data Science laboratory at IRB Barcelona. “This finding challenges the traditional view of how these interactions occur and suggests that we may have missed important cancer-causing events,” he adds.
The “two strikes” model
“Two-hit” events involve a type of genetic alteration, such as a mutation, that occurs in combination with another event, commonly a copy number alteration. This combination amplifies the effects of the individual events and increases the likelihood of developing cancer.
This relationship was well known in hereditary cancer risk variants, such as pathogenic variants in BRCA1 gene, which cause breast and ovarian cancer. Here the researchers focused on less-studied "second hits" that involve somatic (i.e., non-hereditary) mutations. The discovery that these events are common drivers in different types of cancer underlines the importance of considering the combination of different types of mutations in genomic analyses.
Scientists developed a new method called MutMatch to study the combined effects of mutations and copy number alterations in cancer. They analyzed genetic data from about 18,000 tumors to discover patterns of genetic changes.
«The study was based on the exhaustive analysis of 18.000 cancer genomes»
Dr. Elizaveta Besedina (IRB Barcelona)
“These double-hit events are crucial for understanding the later stages of tumor progression. "They establish complex interactions between different genetic changes and how they collectively contribute to cancer," says the Dr. Besedina, first author of the study.
New therapeutic approaches
This research provides a roadmap for future research in cancer genetics. By exploring the interactions between different types of genetic changes, scientists can gain a deeper understanding of how cancer develops and progresses. This knowledge could lead to the development of new, more effective treatments for the disease.
Understand the interaction between mutations and alterations in copy number allows scientists to identify new targets for therapies against cancer, including previously overlooked targets such as tumor suppressor genes. Since these genes have been shown, paradoxically, to also drive cancer through increases in copy number, this suggests that many mutations in them are so-called “dominant negative” mutations.
These are, in principle, attackable by therapies. This is how this new genetic knowledge could lead to the identification of new anti-cancer drugs or the reuse of existing ones, potentially enhancing their effectiveness.
Finally, knowledge of the diverse genetic landscapes of tumors can help stratify patients into more precise subgroups and thus contribute to guide treatment approaches training and potentially identify additional groups of patients who could benefit from current therapies.

Source: SINC Agency
Image: National Human Genome Institute
Reference: Elizaveta Besedina & Fran Supek. «Copy number losses of oncogenes and gains of tumor suppressor genes generate common driver mutations». Nature Communications.La Javie, 2024