Clinicalomics: Most of us have used a mapping app at some point, whether for driving directions, finding the best route to the closest subway stop, or just to look at places on the globe we might like to visit one day. The power of these programs is derived from their ability to zoom in on discreet locations within large cities or being able to zoom out to get an overview of how to travel from point A to point B. Imagine now that this was possible for the cancer genome.
Researchers at the University of Wisconsin-Madison are not
conceptualizing this technology, as they have developed a new approach
that will account for both the discreet locations and a global content
of the genome at once. Ultimately, this should enable researchers and
clinicians to look at the small- and large-scale genetic changes that
define individual cancers.
"Cancer genomes are complicated but we found that, using an approach
like this, you can begin to understand them at every level," stated
David Schwartz, Ph.D. professor of genetics and chemistry at the
University of Wisconsin-Madison and senior author on the current study.
The findings from this study were published recently in PNAS through an
article entitled "Single-molecule analysis reveals widespread
structural variation in multiple myeloma."
While the technique and study results are still preliminary, Dr.
Schwartz is excited for others to test what he and his colleagues found.
Moreover, the results demonstrate the potential of the approach the
investigators took, which combines a system called optical mapping with
more traditional genomic tools like DNA sequencing
"The approach allows an intimate view of a cancer genome," Dr. Schwartz
explained. "You get to see it, you get to measure it, and you get to
see it evolve at many levels. This is what we should be doing with every
cancer genome and the goal here is to make the system fast enough so
this becomes a routine tool."
Specifically, Dr. Schwartz and his team isolated DNA from normal and
cancerous tissue from a patient with multiple myeloma at two different
stages of the illness: when the cancer was responsive to drug treatment
and at a point when it had become resistant to chemotherapy.
First, the researchers performed standard DNA sequencing to obtain the
zoomed in portion of the genome. Then DNA was stretched out and placed
in a special device. The strands were given specific landmarks and
marked with a fluorescent dye. An automated system took images of each
of these marked segments, cataloging the molecules, much like a barcode,
into large datasets that were then pieced together like a jigsaw puzzle
to provide a zoomable view of the genome.
"It's a rare, near-complete characterization of the complexity of a
myeloma genome, from the smallest variance all the way to big chunks of
chromosomal material that differ between the tumor DNA and the normal
DNA of the patient," stated co-author Fotis Asimakopoulos, M.D., Ph.D.,
professor of medicine and a multiple myeloma researcher and physician at
the UW-Madison School of Medicine and Public Health.
What they found was that across the two time points from when the
samples were taken the multiple myeloma genome was marked by an increase
in notable mutations and larger scale changes. Not only were there more
unusual mutations as the cancer progressed, but whole sections of the
genome were removed, flipped around, or even inserted.
"To cure myeloma, we need to understand how genomes evolve with
progression and treatment," said Dr. Asimakopoulos. "The more we can
understand the drivers in cancer in significant depth, and in each
individual, the better we can tailor treatment to each patient's disease
In the meantime, Dr. Schwartz and his team continue to work toward
advancing the system making it higher-resolution, more cost-effective
and scalable. The researchers would ultimately like to build a system
capable of analyzing 1,000 genomes in 24 hours.