What causes a healthy cell to turn cancerous or a sedentary tumor cell to venture into the blood stream and invade a distant organ? Researchers hope to answer these critical questions in a pilot project meant to catalogue the myriad gene changes that can lead to cancer.

The project, funded by the National Cancer Institute and the National Human Genome Research Institute, two divisions of the National Institutes of Health, will focus on three types of cancerous tumors still to be determined. It is actually a test run for a much larger – and more controversial – cancer genome project aimed at identifying all the genetic abnormalities that underlie cancer.

An original $1.35 billion plan, proposed last February by the Broad Institute’s Eric Lander, aimed to sequence DNA from thousands of tumors in the 50 most common types of cancer. That proposal brought criticism from some cancer researchers, however, who questioned whether such a Herculean project would be a wise use of funds.

Results from the pilot project will be used to shape a more comprehensive analysis, called the Cancer Genome Atlas.

Of the new pilot project, Francis Collins, director of National Human Genome Research Institute (NHGRI), says, “We want to see that this has promise in changing the clinical approach to cancer…We expect discoveries that will identify new drug targets and stratify cancers into different subtypes with different diagnostics and therapeutics.”

The genetic mutations that characterize cancer vary, both between cancer types and within a single tumor. For example, a series of genetic missteps might lead to the formation of a primary tumor, while another series of abnormalities within a single cell in that tumor could allow the cancer to spread to other organs. Further, the same type of tumor in another person might follow a different genetic path. So a complete cancer genome “atlas” will require the sequencing of thousands of tumors to identify all the mutations that can turn a cell cancerous.

Advocates of the effort at the NIH say rapid progress in genetic sequence and analysis technologies make this the right time to embark on such an ambitious project. At the start of the human genome project, sequencing cost $10 per base of DNA; it’s now down to one-tenth of a penny, and the price continues to drop.

The pilot project will provide grants to cancer and sequencing centers across the nation to analyze hundreds of tumor samples for gene variations and larger-scale structural changes, such as gene duplications and deletions. And the findings will be compiled in a massive central database that will be publicly accessible.

“This is like the beginnings of the human genome project,” says Richard K Wilson, a geneticist at the Washington University School of Medicine in St. Louis, MO. “We are putting our heads together and pooling our resources to figure out how to bring technology to bear on the cancer field.”

Wilson is looking for genes involved in tumor metastasis, the crucial step when cancer cells migrate away from the original tumor and produce cancers in other tissues. To do this, they look for genetic differences in two tumors, one that metastasized and one that did not. “To answer that question, you need to look at a lot of sequence,” says Wilson.

His group and others will also test some new technologies that will be crucial for a larger-scale project, including novel sequencing machines that can drastically reduce the time and money needed to read a cancer cell’s genome. The National Cancer Institute and NHGRI are also asking for proposals outlining high throughput methods to analyze epigenetics – indirect factors, such as DNA methylation, that affect gene expression.

Other researchers, such as Matthew Meyerson of the Dana-Farber Cancer Institute and Harvard Medical School in Boston, plan to look directly for mutations in potential drug targets, such as the enzymes implicated in cancer. Last year, Meyerson’s lab and another research group independently identified the mutation that makes some lung cancer tumors respond well to the drugs Iressa and Tarceva.

However, some scientists still question whether the pilot project will be worth the investment. “You have to ask, is this the best use of money for solving the problem of cancer?” says Stephen J. Elledge, a geneticist at Harvard Medical School, who is concerned that the project will take money away from other cancer research efforts.

“We understand everyone’s anxiety about the constrained [NIH] budget, but that’s not a reason not to do it,” NHGRI’s Collins told Technology Review.

Prior to advancing to the next phase, the institutes will evaluate the three-year pilot project to determine how efficient it has been in collecting data, and how well that data has translated into clinic, Collins says.