Mapping mutation `hotspots' in cancer reveals new drivers and biomarkers


Date:
February 9, 2022
Source:
University of California - San Diego
Summary:
Researchers have identified a previously unrecognized key player
in cancer evolution: clusters of mutations occurring at certain
regions of the genome. These mutation clusters contribute to
the progression of about 10% of human cancers and can be used to
predict patient survival.



FULL STORY ========================================================================== Researchers led by bioengineers at the University of California San
Diego have identified and characterized a previously unrecognized key
player in cancer evolution: clusters of mutations occurring at certain
regions of the genome.

The researchers found that these mutation clusters contribute to the progression of about 10% of human cancers and can be used to predict
patient survival.


==========================================================================
The findings are reported in a paper published Feb. 9 in Nature.

The work sheds light on a class of mutations called clustered somatic
mutations -- clustered meaning they group together at specific areas in a cell's genome, and somatic meaning they are not inherited, but caused by internal and external factors such as aging or exposure to UV radiation,
for example.

Clustered somatic mutations have so far been an understudied area in
cancer development. But researchers in the lab of Ludmil Alexandrov,
a professor of bioengineering and cellular and molecular medicine at
UC San Diego, saw something highly unusual about these mutations that
warranted further study.

"We typically see somatic mutations occurring randomly across the
genome. But when we looked closer at some of these mutations, we saw
that they were occurring in these hotspots. It's like throwing balls
on the floor and then suddenly seeing them cluster in a single space,"
said Alexandrov. "So we couldn't help but wonder: What is happening
here? Why are there hotspots? Are they clinically relevant? Do they tell
us something about how cancer has developed?" "Clustered mutations have largely been ignored because they only make up a very small percentage
of all mutations," said Erik Bergstrom, a bioengineering PhD student
in Alexandrov's lab and the first author of the study. "But by diving
deeper, we found that they play an important role in the etiology of
human cancer." The team's discoveries were enabled by creating the most comprehensive and detailed map of known clustered somatic mutations. They started by mapping all the mutations (clustered and non-clustered) across
the genomes of more than 2500 cancer patients -- an effort that in total encompassed 30 different cancer types. The researchers created their map
using next-generation artificial intelligence approaches developed in
the Alexandrov lab. The team used these algorithms to detect clustered mutations within individual patients and elucidate the underlying
mutational processes that give rise to such events.

This led to their finding that clustered somatic mutations contribute
to cancer evolution in approximately 10% of human cancers.



========================================================================== Taking it a step further, the researchers also found that some of the
cancer- driving clusters -- specifically those found in known cancer
driver genes - - can be used to predict the overall survival of a
patient. For example, the presence of clustered mutations in the BRAF
gene -- the most widely observed driver gene in melanoma -- results in
better overall patient survival compared to individuals with non-clustered mutations. Meanwhile, the presence of clustered mutations in the EGFR
gene -- the most widely observed driver gene in lung cancer -- results
in decreased patient survival.

"What's interesting is that we see differential survival in terms of
just having clustered mutations detected within these genes, and this
is detectable with existing platforms that are commonly used in the
clinic. So this acts as a very simple and precise biomarker for patient survival," said Bergstrom.

"This elegant work emphasizes the importance of developing AI
approaches to elucidate tumor biology, and for biomarker discovery
and rapid development using standard platforms with direct line of
sight translation to the clinic," said Scott Lippman, director of
Moores Cancer Center and associate vice chancellor for cancer research
and care at UC San Diego. "This highlights UC San Diego's strength in
combining engineering approaches in artificial intelligence for solving
current problems in cancer medicine." A new mode of cancer evolution
In this study, the researchers also identified various factors that
cause clustered somatic mutations. These factors include UV radiation,
alcohol consumption, tobacco smoking, and most notably, the activity of
a set of antiviral enzymes called APOBEC3.



========================================================================== APOBEC3 enzymes are typically found inside cells as part of their internal immune response. Their main job is to chop up any viruses that enter
the cell.

But in cancer cells, the researchers think that the APOBEC3 enzymes may
be doing more harm than good.

The researchers found that cancer cells -- which are often rife with
circular rings of extrachromosomal DNA (ecDNA) that harbor known cancer
driver genes - - have clusters of mutations occurring across individual
ecDNA molecules. The researchers attribute these mutations to the activity
of APOBEC3 enzymes. They hypothesize that APOBEC3 enzymes are mistaking
the circular rings of ecDNA as foreign viruses and attempt to restrict
and chop them up. In doing so, the APOBEC3 enzymes cause clusters of
mutations to form within individual ecDNA molecules. This in turn plays
a key role in accelerating cancer evolution and likely leads to drug resistance. The researchers named these rings of clustered mutations
kyklonas, which is the Greek word for cyclones.

"This is a completely novel mode of oncogenesis," said Alexandrov. Along
with the team's other findings, he explained, "this lays the foundation
for new therapeutic approaches, where clinicians can consider restricting
the activity of APOBEC3 enzymes and/or targeting extrachromosomal DNA for cancer treatment." This work was supported by a Cancer Grand Challenge
award from Cancer Research UK as well as funding from the U.S. National Institutes of Health, Alfred P.

Sloan Foundation, and Packard Foundation.

========================================================================== Story Source: Materials provided by
University_of_California_-_San_Diego. Original written by Liezel
Labios. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. 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; DOI: 10.1038/s41586-022-04398-6 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220209112102.htm

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