Tumor suppressor genes as therapeutic targets

It was known that these two types of changes interact to cause cancer, but there had been no systematic studies detailing the mechanism of action. Scientists from IRB Barcelona published new findings in Natural communicationsshowing that cancer progression is significantly influenced by the interaction between gene copy number changes and mutations.

The study confirms previous studies suggesting that copy number reduction correlates with mutations in tumor suppressor genes (interfering with their protective functions against cancer), while copy number increase correlates with more mutations in oncogenes that promote cancer development.

Unexpectedly, the researchers also found a link between increased gene copy number and mutations in tumor suppressor genes, as well as a link between lower copy number and higher mutations in various oncogenes. The team noted that paradoxical relationships between mutations and copy number are common in cancer genomes.

Genetic changes in cancer

Researchers, Dr. Elizaveta Besedina And Dr. Fran Supekprovided new insights into the role of genetic alterations in cancer development, opening up new avenues for considering tumor suppressor genes as potential targets for cancer treatment.

“Our study shows that both increases and decreases in gene copy number can occur in surprising ways to drive cancer evolution,” explains the researcher. Dr. Supekhead of the genomic data lab at IRB Barcelona and professor at the Centre for Biotechnology Research and Innovation at the University of Copenhagen. “This discovery challenges the traditional view of how these interactions occur and suggests that we may have missed important events that cause cancer,” he adds.

Second-Strike Events (or “Two-Strike Model”): A Common Feature of Cancer

“Two-hit” events involve a type of genetic change, such as a mutation, that occurs in combination with another event, usually a copy number change. This combination amplifies the effects of the individual events and increases the likelihood of developing cancer.

This link has been well established in inherited cancer risk variants, such as pathogenic variants of the BRCA1 gene that cause breast and ovarian cancer. Here, the researchers focused on less-studied “second hits” associated with somatic (i.e., non-inherited) mutations. The discovery that these events are common drivers across cancer types highlights the importance of considering the combination of different mutation types in genomic analysis.

Scientists have developed a new method called MuteMatch to study the combined effects of mutations and copy number changes in cancer. They analyzed genetic data from about 18,000 tumors to look for patterns of genetic changes.

“These dual events are critical to understanding the later stages of tumour progression. “They establish complex interactions between different genetic alterations and how they collectively contribute to cancer development,” says the researcher. Dr. Besedinafirst author of the study.

Towards new therapeutic approaches

This study provides a roadmap for future research into cancer genetics. By studying 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.

Understanding the interactions between mutations and copy number changes allows scientists to identify new targets for cancer treatment, including previously overlooked targets such as tumor suppressor genes. Because these genes have been shown, paradoxically, to also cause cancer by increasing their copy number, this suggests that many mutations in them are so-called “dominant negative” mutations. In principle, these could be attacked with therapy. This is how this new genetic knowledge could lead to the identification of new cancer drugs or the repurposing of existing ones, potentially increasing their effectiveness.

Finally, knowledge of the diverse genetic landscape of tumors may help to stratify patients into more precise subgroups and thus help develop personalized treatment approaches and potentially identify additional patient groups that may benefit from modern therapies.

The research was funded by the ERC, the Generalitat of Catalonia and the Spanish Ministry of Science and Innovation.

Reference article:

Elizaveta Besedina and Fran Supek. The loss of oncogene copy number and the appearance of tumor suppressor genes lead to common mutations that lead to the development of cancer in humans. Natural communications (2024) DOI: 10.1038/s41467-024-50552-1

Fountain: IRB Barcelona