Certain genes are known to cause cancer, and surprising new research shows why: Mutations in non-coding regions become functional, changing the abundance of messenger RNA, or mRNA, and potentially facilitating cell proliferation . Even more surprising, the number of mutations in these regions can predict how long patients survive for certain types of cancer.
DNA – illustrative photo. Image credit: Pixabay (Free Pixabay license)
Most genes are a DNA sequence that contains the recipes for producing proteins. Proteins, in turn, are chains of amino acids that the body uses to send signals between cells, build and repair tissues, and countless other functions necessary for life. Within these genes, some areas are directly translated into proteins, while others, called noncoding regions, do not directly contribute to protein production.
But these silent, non-coding regions are far from lazy. They act much like a basketball coach during a game, directing the active regions of the gene to increase or suppress their expression, thereby playing a crucial regulatory role.
Mutations in these non-coding areas are relatively common, but were once thought to have minimal impact on an organism’s functions because they did not change a protein’s recipe. But what happens to their regulatory functions when a mutation occurs?
UCLA researchers now have an answer. Mutations in these non-coding areas are relatively common, but were once thought to have minimal impact on an organism’s functions because they did not change a protein’s recipe. But UCLA researchers have made an important discovery: these mutations lead to the production of abnormal amounts of mRNA. mRNA serves as a messenger for DNA, carrying the pattern of protein production from the cell nucleus to the cytoplasm, where proteins are synthesized.
When mutations cause changes in mRNA levels, it can lead to excess or deficiency in protein production, similar to the culinary disaster of mistaking a teaspoon for a cup of salt in a recipe. Since cancer involves uncontrolled growth of cells, the abundance of mRNA could activate – or fail to inhibit – cell proliferation, ultimately leading to tumors and cancer.
The researchers made the discovery by synthesizing thousands of mutations in fully functional DNA reporters – a type of gene that helps scientists study what a gene expresses – which they introduced into cells, then analyzed the resulting changes in mRNA abundance. The results were published in the journal Nature Communications.
“Predicting the outcomes of mutations in protein-coding regions is relatively simple, but understanding the functions of mutations in non-coding regions presents a significant challenge,” said the corresponding author. Xinshu “Grace” Xiao, professor of integrative biology and physiology at UCLA. “We designed a high-throughput experiment capable of evaluating a wide range of mutations simultaneously. »
Some non-coding mutations are so rare that they only occur in a few individuals. Additionally, each person has their own mutations. Rare mutations are difficult to study because their rarity means it is difficult to obtain them in statistically significant quantities.
“We focused on these poorly understood rare mutations because with our method we could generate an unlimited number of them, providing an unprecedented opportunity to understand what they do,” Xiao said.
This exploration led to a completely unexpected discovery: many of the rare functional mutations were associated with genes linked to cancer pathways.
This discovery directed research towards the selection of genes known to cause cancer. These notorious cancer-causing genes have many somatic mutations – acquired during the individual’s lifetime rather than through inheritance – in non-coding regions that are not understood. The team repeated their experiments, this time testing for 11,929 somatic mutations in 166 cancer-causing genes.
They found that a large fraction – 33% – of somatic mutations in the non-coding regions of 155 of the 166 cancer driver genes tested can change mRNA abundance. But Xiao’s group didn’t stop there. They combed a cancer database for patients with these rare mRNA-modulating mutations and found many. Turning that stone over revealed an even bigger surprise.
“The number of functional mutations in untranslated regions can predict patient survival for certain types of cancer,” said Ting Fu, first author of the paper and a postdoctoral researcher in Xiao’s lab. “We called this measure “untranslated tumor mutation burden” or uTMB and found the association between uTMB and squamous cell carcinoma of the lung as well as head and neck squamous cell carcinoma particularly striking.
This discovery opens new avenues for the development of prognostic testing tools. By calculating uTMB for each patient, healthcare professionals could obtain valuable predictions regarding survival outcomes to guide the selection of the most effective treatment options.
The results also signal a promising new direction for research into the genetic regulatory mechanisms involved in cancer. Understanding how these mutations influence mRNA abundance – and by extension, protein production – could shed light on the complex processes that lead to cancer progression.
“Our next goal is to uncover the precise regulatory mechanisms by which these mutations operate in cancer cells. Given their impact on mRNA levels, the underlying mechanisms could be of crucial importance for the advancement of cancer treatment,” said Xiao.
This work was supported by grants from the National Institutes of Health.
Written by
Source: UCLA
Originally published in The European Times.
source link eu news
