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 testing.

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 therapeutic strategies."

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' formation.

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 tumors.

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 Cancer Institute.