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The microarray way
Genetic fingerprinting is done with DNA microarray technology, using devices that can quickly determine which of the approximately 25,000 genes in human cells are active and which are inactive. The reams of data generated by microarray scans – and the great variety of gene-activity patterns in ovarian tumors – make tracing the genetic roots of platinum resistance a daunting undertaking.
The Dana-Farber team has risen to the challenge with an approach that goes beyond pure data sorting. "DNAscanning technologies are changing the way we think about collecting and analyzing data," Dr. Quackenbush says. "Research emerging from the Human Genome Project is moving the biological sciences closer to the information sciences. In this project, we're drawing not only on microarray data, but also on the medical literature on ovarian cancer, which covers decades of research into this disease."
In the study, researchers obtain fresh ovarian cancer samples from patients undergoing surgery and from the Dana-Farber/Brigham and Women's Cancer Center tumor bank. (For a closer look at the bank and the procedure, developed by Dr. Drapkin, for collecting and analyzing fresh tumor tissue, see Researchers "bank" on tissue collections.) The samples are fed into microarray devices, which produce grids showing genes' level of activity, or "expression." Grids from all samples are then compared to pinpoint genetic differences between platinum-sensitive and platinum- resistant tumors.
But researchers want to know more than simply where these differences lie. Knowing what the affected genes do – which processes they carry out – could provide clues to the basic mechanisms of platinum resistance and could spark ideas for novel therapies that neutralize the resistance.
To gain such insights, Dr. Quackenbush and his colleagues have created a data "warehouse" on genes involved in ovarian cancer. From material available on the Internet, they've downloaded information on the human genome, the role of individual genes, the signaling pathways between them, and the effect of specific gene alterations. The data bank serves as a repository of scientific knowledge to apply to the results of microarray scans.
"We live in an information-rich world, but the challenge is to bring data together and arrange it in ways that are useful," Dr. Quackenbush remarks. "The database we've created is similar to having all the books one needs in a single library, rather than having to go from place to place to get them."
The researchers had scanned tissue from about 30 ovarian tumors by mid-2007 and plan to scan 200 by the time the study is complete. They have isolated a small number of genes whose activity levels are different in platinumsensitive tumors from those in resistant ones. When Dr. Quackenbush and his team looked up the role of these genes in their data base, they found many of them are involved in copper transport within cells. That grabbed their attention: Some studies suggest that genes involved in copper transport also play a role in conveying platinum out of cells.
"Although the number of tissues we've screened is still small, the results suggest a mechanism for resistance – that cells eventually gain the ability to pump platinum out of themselves," Dr. Quackenbush states. "If we can validate these genes' involvement in additional samples, we'll be in a position not only to test tumors to determine if they're platinum resistant, but also to begin thinking about ways of blocking the resistance mechanism."
This type of research is possible only because of the breadth of expertise we can bring to bear on it, he continues. "With a study of this complexity, the only way to make headway is with a group of people who span a range of disciplines from the clinic to the laboratory to the computer. We're fortunate to work in that kind of environment."
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