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Repetitive DNA sequences may play a role in certain types of cancer, and the Stanford medical researchers and their colleagues created a molecule that targeted
it.
Research led by scientists at Stanford University School of Medicine suggests that long, repetitive DNA sequences may play a role in gene regulation in 7 types of cancer, and that there may be a way to control these sequences to inhibit cancer cell reproduction
.
Using a new algorithm, the researchers analyzed more than 2,000 human cancer genomes, first identifying these repeats, then creating a molecule in kidney cancer cells that targets them, finding that it slowed the production of these cells and sometimes even killed them
.
Although scientists aren't sure what role these repetitive sequences play in cancer, they seem to have found a way to inhibit the production of more cancer cells, which is encouraged
.
"The most compelling result is that you can actually target them and stop cells from proliferating," said
Michael Snyder, Ph.
D.
, a professor and professor in the Department of Genetics.
Snyder is the senior author of the study, which was published Dec.
14 in the journal Nature
.
Graham Erwin, Ph.
D.
, a postdoctoral scholar at the Stanford Cancer Institute, is the lead author.
The project did not start with cancer, but with a rare, incurable neurodegenerative disease, Friedrich ataxia
.
Five years ago, Erwin, then a graduate student at the University of Wisconsin-Madison, was exploring the genetic basis of Friedrich's ataxia in hopes of filling a therapeutic gap
.
Erwin knew that DNA mutations known as repeated amplification could cause Friedrich's ataxia, as well as dozens of other serious diseases, many of them neurological
.
Repeat expansion is an extension
of DNA that mistakenly repeats itself tens to thousands of times in the genome.
Erwin developed a molecule called Syn-TEF1, which focuses on the repetitive expansion
that causes Friedreich's ataxia.
These amplifications destroy the FXN gene and prevent RNA polymerases (molecules that transcribe DNA into RNA (molecular formulas for proteins) from correctly transcribing the gene, allowing cells to produce the corresponding protein, frataxin
.
At healthy levels, frataxin helps the cell's power station mitochondria produce energy and protects cells from active molecules called free radicals
, which are harmful.
Without RNA instructions, cells can't produce the proteins they need, which is especially harmful
to the nervous system and heart, which need energy.
Erwin tested the molecule in cells from Friedrich ataxia patients and found that Syn-TEF1 successfully targeted repeat amplification, helping RNA polymerase transcribe the FXN gene through it, returning frataxin to normal levels
.
Because of its success in cells, researchers are now testing the safety and dosage
of Syn-TEF1 in Friedrich ataxia patients.
When Erwin came to Stanford, he wondered what role
repetitive expansion played in other diseases.
Scientists have yet to discover the role of repetitive dilation in non-neurological diseases, but Erwin doesn't think it's because these mutations aren't present
.
"I think it's just because we haven't looked into it
carefully," he said.
Long repetitive segments of DNA
are difficult to find in cancer genomes.
The most commonly used cancer genome sequencing technology only sequences fragments of DNA
.
These fragments are then used to piece together the entire genome
.
But repeat expansions are usually longer than fragments, which can make lengthy repetitions hidden in plain sight
.
The team found a way
around this hurdle.
"We were able to use a tool that allowed us to find extensions
of sequences from the entire genome," Erwin said.
With this new tool, Erwin and his colleagues extracted 2622 cancer genomes from 2509 patients, with data from the International Cancer Genome Alliance and Cancer Genome Atlas
.
Due to the lack of research on the repeated expansion of cancer, it is unclear what they will find, if any
.
But of the 29 different cancers they examined, the team found 160 duplicate amplifications in 7
cancers.
They further found that 155 of the repetitive dilations were specific to certain cancer subtypes — "which means," Erwin said, "that if we detect (some repetitive dilations) in prostate cancer, we tend not to detect them
in other cancers.
" ”
To make sure they found repeated expansions that were both cancer-specific and longer than normal, the researchers compared
each person's cancer cell genome to that of non-cancer cells.
Duplicate DNA sequences are found in healthy genomes, but the expansion of these sequences can lead to disease
.
Repeat amplification is most common in prostate and liver cancer, and the researchers detected duplicates
in 93 percent of the prostate cancer genome and 95 percent of the liver cancer genome.
This duplication also occurs in
ovarian cancer, kidney cancer, a type of brain cancer called hairy cell astrocytoma and a type of lung cancer called squamous cell carcinoma.
However, it is possible that there are more duplicate dilations
in the cancer genome that researchers can't detect.
As sequencing technology advances in analyzing longer DNA fragments, Snyder predicts they will find more duplicate fragments in different cancers
.
"I think we're just the tip of the iceberg," he said
.
To see if their findings could lead to new directions in cancer treatment, the researchers drew on Erwin's earlier work to create a molecule called Syn-TEF3 to target specific repetitive expansions in kidney cancer cells and compare
it to molecules without the ability to target.
With Syn-TEF3-specific repeat amplification, Syn-TEF3 slows or kills cell production
.
In cells without this swelling, this molecule has little effect
.
Similarly, molecules that do not target repeated expansion do not confer benefits from Syn-TEF3
, the researchers reported.
"It's quite unusual to go from discovery directly to potential therapeutic pathways," Snyder said
.
Researchers still have a long way to go before testing their method in humans, but Snyder and his team are excited
to explore it.
