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The findings were published in the February 9 issue of the journal Nature
.
The study uncovered a class of mutations known as aggregated somatic mutations - aggregates meaning they clump together in specific regions of a cell's genome, while somatic means they are not inherited but caused by internal and external factors , such as aging or exposure to UV radiation
.
So far, aggregated somatic mutations have been an under-studied area of cancer development
.
But researchers in the lab of Ludmil Alexandrov, professor of bioengineering and cellular and molecular medicine at UC San Diego, found that these mutations are so unusual that they warrant further study
"We usually see random somatic mutations in the genome
.
But when we look closely at these mutations, we see that they occur in these hotspots
Erik Bergstrom, a bioengineering doctoral student in Alexandrov's lab and first author of the study, said: "Clustering mutations have been largely ignored because they represent a very small fraction of all mutations
.
But by digging deeper, we found that They play an important role in the etiology of human cancers
The team's discovery was achieved by creating the most comprehensive and detailed map of known aggregate cellular mutations
.
They first mapped all mutations (clustered and non-clustered) in the genomes of more than 2,500 cancer patients, a work that included a total of 30 different cancer types
Going a step further, the researchers also found that some cancer driver clusters—especially those found in known cancer driver genes—can be used to predict overall patient survival
.
For example, the presence of clustered mutations in the BRAF gene, the most widely observed driver gene in melanoma, resulted in better overall patient survival than individuals with non-clustered mutations
"Importantly, we saw that clustered mutations detected from these genes alone could produce differential survival rates that could be detected with existing platforms commonly used in the clinic
.
So this is a very simple and precise Patient Survival Biomarkers
"This excellent work underscores the importance of developing artificial intelligence approaches to elucidate tumor biology, as well as the discovery and rapid development of biomarkers using standard platforms that translate directly into clinical vision
.
" Director, Moores Cancer Center , said Scott Lippman, vice chancellor for cancer research and nursing at UC San Diego
A new model of cancer evolution
In this study, the researchers also identified various factors that contribute to aggregated somatic mutations
.
These factors include UV radiation, alcohol consumption, smoking, and most notably, the activity of an antiviral enzyme called APOBEC3
The APOBEC3 enzyme is normally found inside cells as part of the intracellular immune response
.
Their main job is to cut off any virus that enters the cell
.
But in cancer cells, the researchers think the APOBEC3 enzyme may do more harm than good
.
The researchers found that cancer cells are often filled with loops of extrachromosomal DNA (ecDNA) that carry known cancer driver genes, with clustered mutations within a single ecDNA molecule
.
The researchers attributed the mutations to the activity of the APOBEC3 enzyme
.
They hypothesized that the APOBEC3 enzyme mistook loops of outer DNA for foreign viruses and tried to confine and cut them
.
During this process, the APOBEC3 enzyme leads to the formation of clusters of mutations within a single ecDNA molecule
.
This, in turn, has played a key role in accelerating cancer evolution and potentially leading to drug resistance
.
The researchers named these clusters of mutant rings kyklonas, which is the Greek word for cyclone
.
"This is an entirely new model of tumorigenesis," Alexandrov said
.
Along with the team's other findings, he explained, "this lays the groundwork for new therapeutic approaches that clinicians could consider limiting the activity of the APOBEC3 enzyme and/or targeting the APOBEC3 enzyme.
Cancer therapy of extrachromosomal DNA
.
"
Erik N.
Bergstrom, Jens Luebeck, Mia Petljak, Azhar Khandekar, Mark Barnes, Tongwu Zhang, Christopher D.
Steele, Nischalan Pillay, Maria Teresa Landi, Vineet Bafna, Paul S.
Mischel, Reuben S.
Harris, Ludmil B.
Alexandrov.
Mapping clustered mutations in cancer reveals APOBEC3 mutagenesis of ecDNA .
Nature , 2022
