A groundbreaking study conducted by researchers at UCLA has revealed that mutations in noncoding regions of genes may play a significant role in driving cancer. While most genes are responsible for producing proteins that are essential for various biological functions, certain regions within genes, known as noncoding regions, do not directly contribute to protein production. However, these noncoding regions have been found to regulate the expression of active gene regions, similar to a basketball coach directing players during a game. Mutations in these noncoding regions were previously thought to have minimal impact on the organism’s functions, as they do not alter the protein’s recipe.
The UCLA researchers discovered that mutations in noncoding regions can lead to abnormal levels of messenger RNA (mRNA), which carries the blueprint for protein production from the nucleus to the cytoplasm, where proteins are synthesized. Changes in mRNA levels can result in either an excess or deficit in protein production, potentially leading to uncontrolled cell growth and the development of tumors and cancer. By synthesizing thousands of mutations into fully functioning DNA reporters and analyzing the resulting alterations in mRNA abundance, the researchers were able to identify the impact of noncoding mutations on gene regulation.
By studying rare mutations that are associated with genes linked to cancer pathways, the researchers made the unexpected discovery that many of these functional mutations were connected to cancer driver genes. These cancer driver genes have somatic mutations in noncoding regions that have not been well understood. Further experiments on 11,929 somatic mutations in 166 cancer driver genes revealed that a significant portion of these mutations could change mRNA abundance. The researchers also found that the number of functional mutations in untranslated regions could predict patient survival for certain types of cancer, such as lung squamous cell carcinoma and head and neck squamous cell carcinoma.
This discovery of the predictive potential of noncoding mutations in patient survival opens up new possibilities for the development of prognostic testing tools in cancer treatment. By calculating the untranslated tumor mutation burden (uTMB) for individual patients, healthcare professionals could make more informed decisions regarding treatment options. The findings also suggest a promising new area for research into the gene regulation mechanisms involved in cancer, with a focus on understanding how mutations in noncoding regions influence mRNA abundance and protein production. This knowledge could offer valuable insights into the complex processes driving cancer progression and potentially lead to advancements in cancer treatment.
The researchers’ high throughput experiment allowed them to assess a wide array of mutations, including rare mutations that are challenging to study due to their scarcity. By generating a large number of these rare mutations, the researchers were able to gain a better understanding of their impact on gene regulation. Moving forward, the team plans to further investigate the regulatory mechanisms behind these mutations in cancer cells, with the hope of advancing cancer treatment. The study was supported by grants from the National Institutes of Health, highlighting the importance and potential impact of this research in the field of cancer biology.
