Gene profiles expose cancer cells' weak points
Genetic 'snapshots' of tumor cells aiding cancer diagnosis and drug development
By Richard Saltus
Measuring gene activity in cancer cells, Dana-Farber scientists discovered a genetically unique type of leukemia that strikes infants. Left to right: Scott Armstrong, MD, PhD, Stanley Korsmeyer, MD, and Stephen Sallan, MD, study data from the project.
In their deadly quest to grow and spread, cancer cells are the ultimate stealth weapon. They hide from the body's immune defenses, hijack new blood supplies, and often evade the most toxic drugs thrown against them. Cancer cells' outward appearance can camouflage their true nature. In some types of cancer, one patient's tumor may look just like another's under the microscope, yet in one person the cancer proves curable, while in the other it is lethal. And no one can predict which is which — an uncertainty that bedevils patients and doctors alike and hampers effective treatment.
"Microarrays," or "gene chips," contain pieces of DNA that can identify genes in a cell and determine whether they are active or not. They can detect the on-or-off status of thousands of genes at a time and produce a "gene profile" of the cancer cell.
That's why there's a continual search for better methods of cancer diagnosis, which "stands at the crux of everything we do for cancer patients," says Sridhar Ramaswamy, MD, of DFCI's Adult Oncology Department. "Even now, in the genetic age, this remains a problem because current diagnostic methods don't detect all the complexities that determine a cancer cell's behavior."
Sometimes conventional methods can't even determine which tissue or organ gave rise to the cancer, further hampering diagnosis. But now a revolutionary system of cancer diagnosis and classification is taking shape, based not on cells' appearance or where in the body they originated, but on their genes. Using new technology and information from the human genome project, scientists have begun to sort out cells by differences in the activity of their genes. The new cancer-identifying technique records a cell's gene expression profile, or "signature," by determining which of its thousands of genes are active, and which are silent.
Just in the past year, a crop of reports by scientists at Dana-Farber and collaborators at the Whitehead Institute for Biomedical Research in Cambridge, Mass., has demonstrated how gene profiling is already yielding important new insights into a variety of cancers.
The new cancer-identifying technique records a cell's gene expression profile, or "signature," by determining which of its genes are active and which are silent.
Any cell's behavior is dictated by the specific off-and-on pattern of its genes, just as a chord on the piano is determined by which keys are sounded and which are silent. Genes that are "on," or expressed, are helping to make proteins that operate the cell, and genes that are "off" are not manufacturing proteins. A human cell contains at least 30,000 genes, scientists believe, each able to make one or more proteins.
Cancer, according to researchers, is fundamentally a disease of genes and the proteins they make. Too much of a certain protein, caused by a gene stuck in the "on" position like a malfunctioning switch, can prod a cell into runaway growth. Conversely, a normally growth-suppressing gene that is stuck in the "off" position can allow cells to grow chaotically and form a tumor.
Other abnormal genes help a tumor obtain a new blood supply in the body, break through tissues and spread to other organs. Therefore, the gene profile of a cancer cell compared with that of a normal cell may reveal genes that are altered or abnormal in the cancer cell — and are at the root of the malignancy.
Usually it's a large number of subtle gene changes that add up to cancer. But, on occasion, the profile spots a single bad gene acting dramatically to turn the cell cancerous. Identifying such genes in different cancers, it is hoped, will lead to new drugs specifically designed to target those genes.
This image from a"gene chip" study shows that the newly discovered type of leukemia, MLL (mixed lineage leukemia), has a gene activity pattern different from ALL (acute lymphoblastic leukemia) and AML (acute myelogenous leukemia).
These advances mark the beginning of a revolutionary new system of cancer classification. "The dream is that when someone comes into the hospital," says Ramaswamy, "instead of people stroking their chins, having conferences, and sending the slides to other experts, the diagnosis will be made on the genetic profile of the cancer rather than solely by microscopic appearance."
He headed a team that last year reported it had obtained the gene profiles of 14 types of cancer cells taken from tumors. They said they could tell these 14 varieties apart with 90 percent success using the gene profiles.
Robert Weinberg, PhD, of the Whitehead Institute, a pioneering cancer researcher who made landmark discoveries of how normal genes become cancer-causing "oncogenes," is enthusiastic about the new findings flowing from gene-profiling laboratories.
"These studies hold the promise of being able to classify tumors in ways that are much more useful than the tumor markers used previously," Weinberg explains. "They will tell us whether tumors that have traditionally been lumped together as one type should be divided into a number of distinct subtypes, and whether these subtypes have different prognoses and respond differently to specific therapies."
- Next: Spin-off of the human genome project
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