Sunday, July 25, 2004

Years of detective work tracked genes

By Tim Bonfield
Enquirer staff writer

Tracking down the potential location of a lung cancer gene was much like looking down from orbit and seeing an entire city, and then zooming in on a single street.

But finding the correct street was no simple task.

Getting the breakthrough results, published in the September edition of American Journal of Human Genetics, required using some of the world's newest, most sophisticated medical technology and years of painstaking detective work to track down biological specimens vital to the project.

It also took screening thousands of people with lung cancer - from Ohio to Louisiana to Colorado - to find 52 families that had multiple cases of lung cancer who also were willing and able to provide the blood and tissue samples needed for analysis.

The task, which cost nearly $6 million, took five years and required help from a dozen medical centers and federal agencies.

Finding families

How hard was this? The search started with more than 26,000 people with lung cancer who were referred to eight medical centers nationwide, including more than 6,400 cases at the University of Cincinnati.

Of those, 3,500 families were identified as having two or more cases of lung cancer among blood relatives. Researchers then tried to collect blood and tissue samples from 771 families who reported three or more lung cancer cases that also crossed generations.

Researchers also scoured hospitals nationwide hunting for "tissue blocks" from deceased lung cancer patients. They finally found enough specimens to study from 196 families, including a dozen from Greater Cincinnati.

The search for tissue blocks was so difficult because so many lung cancer victims died without ever having surgery, so samples were never collected. In some cases, hospitals that had tissue samples threw them away. In dozens of cases, experts resorted to using blood samples from spouses and children to statistically "re-create" the genetic makeup of a deceased parent.

Extracting the DNA

From the 196 families, information from 92 families - including blood samples from nearly 650 people and tissue samples from nearly 90 people - were chosen for detailed genetic analysis.

Parts of this work were performed at the National Human Genome Research Institute in Baltimore, Washington University in St. Louis, the University of Texas Southwestern, the MD Anderson Cancer Center in Houston, and the University of Cincinnati. These and other medical centers nationwide have pumped hundreds of millions of dollars into DNA processing equipment and powerful computers and software capable of analyzing massive amounts of genetic data.

Reporting the results

So far, full genetic analyses have been completed for 52 of the 92 families.

From those families, researchers found a powerful, inherited genetic trait, which has been traced to a tiny area along chromosome 6, one of the body's 22 chromosome pairs. Of the estimated 30,000 to 40,000 genes in the human body, this area contains about 50 genes, including some known to play a role in regulating tumor growth.

In lung cancer families, this area may contain a mutation that allows tumors to grow. This trait was found in 67 percent of the 52 families, including 78 percent of the families with four relatives with lung cancer and 94 percent of the families that had at least five lung cancer cases.

Next steps

Researchers already have started sifting through the 50 genes to find the ones that appear most linked to lung cancer, a process that could be complete within weeks or a few months.

Once the gene is found, other studies will be needed to determine how many people might have the gene, and whether it occurs more commonly among various racial and ethnic groups.

A genetic screening test to inform people of their risk of developing lung cancer could be one of the first developments.

People at high risk also may be urged to get chest CT scans to detect early signs of cancer. A race also will begin to develop treatments using that gene as a target.

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