Tumor DNA in spinal fluid could help doctors better monitor childhood
brain cancer

Date:
October 21, 2020
Source:
Michigan Medicine - University of Michigan
Summary:
Researchers have demonstrated that a new liquid biopsy approach
overcomes traditional barriers to quickly and efficiently diagnose
and monitor high-grade pediatric gliomas.



FULL STORY ==========================================================================
For many cancers, doctors are increasingly looking to the DNA that
solid tumors shed into the blood stream to help with diagnosis and
monitoring. But brain cancer has been a different story thanks to the
natural blockade created by the blood-brain barrier.


========================================================================== Researchers at the University of Michigan Rogel Cancer Center and Michigan Medicine C.S. Mott Children's Hospital, however, were optimistic that cerebrospinal fluid could be a valuable source for tumor DNA that could
help monitor and treat pediatric cancer patients with aggressive brain
tumors known as high-grade gliomas.

Not only do the mutations in these tumors change over time, causing
shifts in potential avenues for treatment, the amount of tumor DNA in a patient's spinal fluid can help doctor's know whether changes observed
on a patient's imaging scans are true signs of a tumor's progression or
a merely the body's response to cancer treatments.

"We knew from past research that the genetic sequences of these tumors, including information about the mutations that are driving them, can
be found in the spinal fluid -- but collecting it isn't currently part
of the standard of care," says Carl Koschmann, M.D., a Mott pediatric oncologist and researcher with the Chad Carr Pediatric Brain Tumor Center
at Michigan Medicine. "That's something we have been hoping to change."
A new study by Koschmann and a team of researchers from U-M suggests new, portable DNA sequencing technology could make such a "liquid biopsy"
approach feasible. The team's findings, which appear in Clinical Cancer Research, a journal of the American Association for Cancer Research,
were the first to apply nanopore genetic sequencing technology toward
this purpose.

"We used a modern, handheld DNA sequencing device in a way that had
never been done before," says study first author Amy Bruzek, M.D.,
a neurosurgery resident at Michigan Medicine. "This allowed us to
analyze the tumor DNA in patients' cerebrospinal fluid quickly and with equipment that's portable enough to bring into the operating room."
The nanopore system works by measuring changes in electrical current as biological molecules pass through the tiny holes in a collection surface; different values correspond to different letters in the genetic code,
thus allowing a DNA sequence to be read.



==========================================================================
The study looked for clinically actionable alternations in samples from 12 patients with high-grade gliomas using a device made by Oxford Nanopore Technologies, a spinout from the University of Oxford. The device costs
about $1,000, weighs one pound and can be connected to a laptop, the researchers note, giving it advantages over leading laboratory models,
which often cost tens of thousands, require dedicated space and are more complex to operate. It also requires significantly smaller amounts of
spinal fluid than other sequencing methods.

Across nearly 130 samples, the researchers found the new approach worked
well, and the results were confirmed using well-established sequencing
methods.

"This study shows an opportunity to efficiently monitor how well clinical
trial medications are working for pediatric glioma patients by collecting spinal fluid at different points in time using a procedure known as
lumbar puncture or spinal tap," Bruzek says.

Currently, after an initial surgery to remove as much of a glioma as
possible, doctors track changes to a tumor by looking at imaging scans.

"Unfortunately, good responses to radiation therapy can create swelling
that looks very similar to a tumor that is growing," Koschmann says. "And
as doctors, we have to tell patients' families the images can't be
interpreted with certainty." Although these pediatric brain cancers
are rare, the vast majority patients who are diagnosed with them live
less than two years. So new, targeted approaches to treating high-grade
gliomas in children and young adults is desperately needed -- including
for diffuse intrinsic pontine gliomas or DIPGs, highly aggressive tumors
of the brain stem.

Exploiting the specific molecular mutations these tumors carry offer
doctors' best hope for attacking them. Sequencing tumor DNA found in cerebrospinal fluid would also allow doctors to monitor how a tumor's
mutations were changing over time and know whether any of the mutations
might make specific treatments less likely to work.

"As caregivers, we're excited about the possibility of monitoring tumors without exposing patients to potential complications from invasive
surgeries," Koschmann says. "This approach suggests we can rapidly
and reliably detect key tumor-driving mutations in high-grade gliomas
with very small samples - - overcoming some of the barriers that were preventing the use of spinal cord fluid in diagnosing and monitoring
these patients. And we're optimistic about incorporating this approach
into clinical trial design for pediatric brain cancer, allowing us to
track molecular response across multiple genes to better understand and
predict clinical outcomes."

========================================================================== Story Source: Materials provided by
Michigan_Medicine_-_University_of_Michigan. Original written by Ian
Demsky. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Amy K. Bruzek, Karthik Ravi, Ashwath Muruganand, Jack Wadden,
Clarissa
May Babila, Evan Cantor, Leo Tunkle, Kyle Wierzbicki,
Stefanie Stallard, Robert P. Dickson, Ian Wolfe, Rajen Mody,
Jonathan Schwartz, Andrea Franson, Patricia L. Robertson, Karin
M. Muraszko, Cormac O. Maher, Hugh J.L. Garton, Tingtin Qin,
Carl Koschmann. Electronic DNA Analysis of CSF Cell-free Tumor
DNA to Quantify Multi-gene Molecular Response in Pediatric
High-grade Glioma. Clinical Cancer Research, 2020; DOI:
10.1158/1078-0432.CCR-20-2066 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201021130148.htm

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