- Besedina, E., Supek, F. Copy number losses of oncogenes and gains of tumor suppressor genes generate common driver mutations. Nat Commun 15, 6139 (2024). https://doi.org/10.1038/s41467-024-50552-1
A research team examined 17,644 cancer exomes and genomes using the MutMatch method to analyse mutations in cancer driver genes. This study identified how copy losses of oncogenes and copy increases of oncosuppressor genes can generate common driver mutations, providing new insights into the mechanisms of positive and negative selection in cancer.
Oncogenes may show signs of positive or negative selection in different gene segments, suggesting that these genes could be drivers or vulnerabilities in specific tumour types. Copy losses of oncogenes are often associated with positive selection, contributing to tumour progression. This phenomenon implies that when one copy of an oncogene is lost, the remaining copy may undergo mutations that promote tumour growth.
Copy number alterations (CNAs) can influence positive selection not only in oncogenes but also in oncosuppressor genes. For example, gene copy number increases can raise the dosage of the mutated allele, intensifying their oncogenic effect. This means that a duplication of a mutated oncosuppressor gene can enhance the effect of mutations, making the tumour more aggressive. The simultaneous presence of point mutations and CNAs may indicate specific selection on a particular driver gene, suggesting that certain genes are crucial for cancer cell survival and proliferation.
The study also identified nine evolutionary archetypes of driver genes, based on the types of genetic alterations affecting them. These archetypes include different combinations of mutations and copy number alterations, which may help identify new driver genes relevant to specific tumour types. For example, certain archetypes may be predominant in lung cancers, while others may be more common in colon cancers.
Positive selection occurs when a mutation provides a selective advantage to the cancer cell, promoting its proliferation. This study showed that mutations in driver genes can be positively selected in different regions of the gene. For example, a mutation in a regulatory region of an oncogene can increase its expression, while a mutation in a coding region can alter the function of the resulting protein. Both of these mutations can provide an advantage to the cancer cell.
Negative selection, on the other hand, occurs when a mutation is deleterious to the cancer cell. This study found signs of negative selection in some oncogenes, suggesting that certain mutations may be detrimental to tumour growth. Understanding these mechanisms may help identify new vulnerabilities in tumours and develop treatments that exploit these weaknesses.
Understanding the interactions between point mutations and NACs could improve molecular diagnosis and patient stratification, allowing for more targeted treatments. Identifying driver genes through this approach could reveal new therapeutic vulnerabilities, allowing the development of specific treatments for patients with particular genetic alterations. For example, a patient with a tumour that has a duplication of a mutated oncosuppressor gene could benefit from a therapy that targets this specific alteration.
Targeted therapies could benefit from knowledge of driver mutations and associated NACs, allowing more precise and potentially more effective interventions. The discovery of new gene drivers may lead to the development of innovative drugs that target specific combinations of mutations. For instance, if a specific mutation in an oncogene is responsible for resistance to a certain drug, a new therapy could be developed to overcome this resistance.
This study offers an advanced insight into the complexity of genetic alterations in cancer, providing crucial new information for clinical research and the development of targeted therapies. The combination of point mutations and gene copy number alterations represents an important area of study for improving the efficacy of cancer treatments. Deepening our understanding of these mechanisms may lead to new therapeutic strategies that improve the prognosis and quality of life of cancer patients.