Scientists say development will enhance cancer gene discovery in humans
Ronald A. DePinho, MD
A team led by Dana-Farber Cancer Institute scientists has developed a
more human-like mouse model of cancer they say will aid the search for
cancer-causing genes and improve the predictive value of laboratory drug
Ronald A. DePinho, MD, of Dana-Farber has created mice that form
tumors that are more genetically complex and unstable — and therefore a
better stand-in for human cancers — than those of conventional
genetically engineered mouse models of cancer. To characterize these
mouse tumors, DePinho collaborated with Lynda Chin, MD, also at
Dana-Farber, to perform high-resolution array-CGH profiling, a
genome-scanning technology that can define regions of DNA abnormalities.
The report has been posted as an advanced online by the journal Nature and will appear in a forthcoming print version.
The scientists, working with a large dataset generated by the Chin
laboratory during the past several years, compared the patterns of these
chromosomal changes in the mice with patterns observed in more than 400
human tumor specimens, including melanoma, lung, colon, and pancreatic
cancers, and multiple myeloma.
The comparisons showed that genetic instability in the mouse cancer
cells caused DNA alterations that in many cases were identical to such
changes in human tumors. This match up, said the researchers, suggested
that the new mouse model may be useful in guiding the search for genes
that are important for cancer growth. To that end, it may facilitate
research associated with the National Institutes of Health-funded Human
Cancer Genome Atlas Project, which involves sifting the entire human DNA
and identifying the immensely complicated, interacting molecular
changes that initiate and maintain tumors.
"We found a rather striking overlap of genetic alterations in the
mouse and human cancers, which should greatly help us sort out genetic
events that drive cancers from those that are simply irrelevant
'passenger' events," DePinho said.
Indeed, using the new 'instability' model of cancer in collaboration
with Michael Stratton, PhD, and Andy Futreal, PhD, at the Wellcome Trust
Sanger Institute in England, the team discovered a pair of gene
mutations involved in a type of human blood cancer.
Stratton, Futreal, Chin, and DePinho are co-senior authors of the report.
As part of the ongoing Cancer Genome Project at the Sanger Institute,
its researchers analyzed human cancer cell lines and clinical samples
to identify the new mutated genes. These studies have uncovered an
unexpectedly large number of genetic alterations present in the typical
human cancer genome, presenting challenges in the identification of
truly causative events.
DePinho said that the overlap in patterns of genetic abnormalities
found in both mouse and human tumors shows that cancer mechanisms in the
two species are more alike than had been thought.
Futreal, co-director of the Cancer Genome Project at the Sanger
Institute, said that such mouse models and cross-species genomic
comparisons will be of "real importance" in facilitating the
identification of new human cancer genes and understanding their role in
the formation of tumors, "as well as a potential avenue to explore new
Conventional mouse models are made by transferring a cancer-causing
oncogene into a mouse embryo. "You plug it into the mouse, and lo and
behold, it gets cancer," explained Richard Maser, PhD, of Dana-Farber,
one of the study's lead authors. "But that's rigging the game — it's not
identical to the process by which tumors normally arise," he said.
These tumors lack some key characteristics of human tumors, such as
genomic instability — pieces of chromosomes breaking apart and
reattaching, which result in widespread abnormalities like missing genes
or extra copies of genes some of which are essential to the tumors'
In the current study, the scientists used gene knockouts to create
mice whose cells lacked crucial molecules whose role is to guard the
genome from instability and chaos in the DNA. As a result, the mice
developed T-cell acute lymphoblastic leukemia/lymphoma, or T-ALL, and
the cancer cells exhibited "rampant genome instability" leading to a
complex pattern of mutations, chromosomal rearrangements, gene
amplifications and gene deletions similar to those in human solid
The mouse model's close resemblance to human T-ALL enabled the scientists to rapidly and efficiently identify two genes, FBXW7 and PTEN, to be commonly deleted or mutated in this type of human cancer.
The research was supported by grants from the National Cancer
Institute, the Wellcome Trust, and the Center for Applied Cancer
Research of the Belfer Institute for Innovative Cancer Science at
Dana-Farber, which DePinho heads.
Dana-Farber Cancer Institute (www.dana-farber.org)
is a principal teaching affiliate of the Harvard Medical School and is
among the leading cancer research and care centers in the United States.
It is a founding member of the Dana-Farber/Harvard Cancer Center
(DF/HCC), designated a comprehensive cancer center by the National