Using a 3D model of the genome, in which DNA is arranged in a fractal globule structure, researchers have demonstrated that the location of a particular stretch of DNA in the globule influences its likelihood of being copied or deleted in a cancer cell. Image: Leonid Mirny and Maxim Imakaev
of the hallmarks of cancer cells is that certain regions of their DNA tend to
get duplicated many times, while others are deleted. Often those genetic
alterations help the cells become more malignant—making them better able to
grow and spread throughout the body.
a team of Massachusetts Institute of Technology (MIT) and Harvard University
researchers has found that the 3D structure of the cell’s genetic material, or
genome, plays a large role in determining which sections of DNA are most likely
to be altered in cancerous cells.
researchers, led by Leonid Mirny, an associate professor of physics and health
sciences and technology, developed a technique to compare the 3D architecture
of chromatin to the chromosomal aberrations often seen in cancer. In the new
study, they showed that any two points that routinely encounter each other are
more likely to form the end of a DNA loop that gets cut out or duplicated.
looks very much like the chromosomal aberrations in cancer, to a large extent,
are shaped by the chromosome’s structure,” Mirny says.
findings, described in Nature Biotechnology, reveal mechanisms and
underlying physical principles governing genome alterations in cancerous cells,
and could help pinpoint locations that host undiscovered cancer-causing or
A new dimension
In 2009, a team of scientists—including Mirny and colleagues from MIT, the
Broad Institute, the University of Massachusetts Medical School (UMMS), and
Harvard—reported the first 3D view of the human genome. Using an experimental
technique developed in the lab of UMMS’ Job Dekker, called Hi-C, and
simulations developed in the Mirny laboratory, they found that the genome is
organized in a structure known as a “fractal globule,” which enables the cell
to pack DNA incredibly tightly while avoiding the knots and tangles that might
interfere with the cell’s ability to read its own genome.
and his colleagues had no plans to use Hi-C to study alterations of the genome
in cancer until a serendipitous conversation arose with scientists at the Broad
Institute. Those researchers, including Gad Getz, the director of Cancer Genome
Computational Analysis at the Broad, and Matthew Meyerson, a senior associate
member of the Broad and professor of pathology at Harvard Medical School, were
studying genetic mishaps—common in cancer cells—known as single copy number
can be deletions of a large region of DNA or duplications of a region—meaning
they could play some role in cancer, since it’s advantageous for a cancer cell
to have many copies of stretches containing oncogenes (cancer-causing genes),
or to delete stretches with tumor-suppressing genes.
and colleagues at the Broad had shown that the probability that a particular
stretch of DNA will be duplicated or excised is inversely proportional to its
length. When Mirny looked at their findings, he noticed a striking similarity
to the Hi-C data: The probability that two particular spots on a chromosome will
come into proximity with each other is also inversely proportional to the length
of the DNA between them.
and Getz decided to test the hypothesis that the 3D structure of the chromosome
influences the likelihood of a particular stretch of DNA being copied or
deleted. To do that, they compared the structure of chromatin predicted by the
fractal-globule model with the locations of common SCNAs found in 3,000 cells
exhibiting 26 different types of cancer.
they found confirmed this idea. “What we see by mathematical modeling is that
the probability of two points coming together in the 3D structure is very close
to the probability of a loop of that length to be amplified or deleted,” Mirny
gives even more evidence to the notion that the physical colocation of
otherwise disparate regions of the genome in the cell is the source of errors
that arise,” says Levi Garraway, an assistant professor of medicine at Harvard Medical School
and a member of the Broad Institute and Dana-Farber Cancer Institute who was
not involved in this research.
DNA repair gone wrong
This work also suggests a possible mechanism by which SCNAs may occur: When two
points are in contact with each other, there is a greater chance that these
points may be joined by mistake during DNA repair.
DNA suffers a break, special enzymes move in to repair it. If two points near
each other are being repaired at the same time, the enzymes may accidentally
attach them to each other, creating a loop that gets cut out of the genome,
says Geoff Fudenberg, a graduate student at Harvard and lead author of the
explains how excisions might occur, but the researchers believe that the
mechanism of creating duplications is likely more complicated.
this study, the researchers also investigated the likelihood of these
alterations spreading through a population of cancer cells. It was already
known that alterations beneficial to the cancer cell are more likely to spread
through the population, while those that are detrimental get eliminated. There
is also a third class of mildly damaging mutations called “passenger
mutations.” In this study, the researchers found evidence that these mutations
also can be selected against. Specifically, the longer the alteration, the more
likely it was to be eliminated.
future studies, the team plans to analyze 3D genome models of different cancer
types, to see if the alterations likely to occur in liver cancer, for example,
differ from those that would occur in lung cancer.
“The more you know about mutational mechanisms, and the more you
understand the landscape of possible mutations in cancer, the better job you’re
going to do at finding genes that are really helping the cancer, and the better
you’ll be able to target those,” Fudenberg says.