noncoding DNA are linked to cancer pathways and can also predict cancer patient survival. By studying tens of thousands of noncoding variants, researchers have gained insight into the function of these mutations and their impact on mRNA and protein production. This discovery could lead to the development of more effective testing tools and a better understanding of the processes underlying cancer progression. Despite the progress made, there is still much to be learned about the functional elements of noncoding DNA.the noncoding regions can have a functional role in changing the levels of messenger RNA, or mRNA, and potentially supporting cell growth. It is even more astonishing that the number of mutations in these regions can predict how long a patient with certain types of cancer will survive.
Most genes are made up of DNA sequences that contain instructions for making proteins. These proteins are made up of chains of amino acids, which the body uses to communicate between cells, build and repair tissues, and perform numerous other functions essential for life. Some parts of these genes are directly used in making proteins, while other parts, known as noncoding regions, have different roles, as explained above.Noncoding regions, although they do not directly contribute to protein production, are not idle. Instead, they play an essential regulatory role by directing the active regions of the gene to either enhance or suppress their expression. This is similar to the role of a basketball coach during a game. Mutations in these noncoding areas are relatively common, and previously it was believed that they have minimal impact on an organism’s functions because they do not change a protein’s recipe. However, researchers at UCLA have now discovered that mutations in these noncoding areas do affect their regulatory duties.Mutations are quite common and were previously believed to have little impact on an organism’s functions because they don’t change a protein’s instructions. However, UCLA researchers found that these mutations actually result in the production of abnormal amounts of mRNA. mRNA acts as a messenger for DNA, carrying the instructions for protein production from the cell nucleus to the cytoplasm, where proteins are made.
When mutations cause changes in mRNA levels, it can result in either an excess or a deficiency in protein production, similar to the culinary disaster of mistaking a teaspoon for a cup of salt in a recipe. Because cancer involves theUncontrolled cell growth, along with an overabundance of mRNA, can either trigger or fail to suppress cell proliferation, ultimately leading to the formation of tumors and cancer.
By introducing thousands of mutations into fully operational DNA reporters, the researchers uncovered this phenomenon. DNA reporters are genes that allow scientists to study the expression of other genes. They then introduced these reporters into cells and examined the resulting changes in mRNA levels. The results of their study were detailed in the scientific journal Nature Communications.
“While it is relatively easy to predict the effects of mutations in protein-coding regions, the same cannot be said for the impact of mutations on mRNA abundance.Understanding the roles of mutations in noncoding regions is a difficult task,” stated Xinshu “Grace” Xiao, a UCLA professor of integrative biology and physiology and the corresponding author of the study. “We developed an experiment with high throughput capabilities to evaluate a wide range of mutations at the same time.”
Some noncoding mutations are extremely uncommon, occurring in only a small number of individuals. Additionally, each person has their own set of unique mutations. Because rare mutations are hard to come by in large enough numbers to be statistically significant, they pose a challenge for research.
“Our focus was on these poorly understood rare mutations, as our method allows us to study them in a efficient manner.”By harnessing the power of CRISPR, we have the potential to create a multitude of mutations, allowing us to learn more about their functions,” stated Xiao. This investigation led to an unexpected revelation: a significant number of these rare, operational mutations were connected to genes associated with cancer pathways. This discovery prompted the focus of the research to shift towards identifying genes that are recognized as drivers of cancer. These well-known cancer driver genes have numerous somatic mutations, acquired over an individual’s lifetime rather than being inherited, in noncoding regions that are not yet fully understood. In a subsequent experiment, the team tested 11,929 somatic mutations.In 166 cancer driver genes, they found that 33% of somatic mutations in noncoding regions can alter mRNA levels. Additionally, they searched a cancer database and found many patients with these rare mutations that affect mRNA. This led to the unexpected discovery that the number of functional mutations in untranslated regions can actually predict patient survival for specific cancer types. Ting Fu, the first author of the article and a postdoctoral scholar in Xiao’s lab, expressed, “We ca.”The researchers labeled this measure as ‘untranslated tumor mutation burden’ or uTMB and discovered a strong connection between uTMB and lung squamous cell carcinoma as well as head and neck squamous cell carcinoma.”
This discovery presents new opportunities for creating predictive testing tools. By determining uTMB for each patient, medical professionals could obtain important insights into survival prospects, which could help in choosing the most suitable treatment methods.
The results also point towards a hopeful new path for studying the gene regulation mechanisms involved in cancer. Understanding The impact of mutations on mRNA abundance, and consequently, protein production, may provide insights into the complex processes involved in driving the progression of cancer. Xiao stated, “Our next goal is to understand the specific regulatory mechanisms through which these mutations operate in cancer cells. Given their influence on mRNA levels, these underlying mechanisms could be crucial for the development of cancer treatments.” This research was supported by grants from the National Institutes of Health.
