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Researchers detail cancer DNA damage

Work paves way to map disease

Email|Print| Text size + By Scott Allen
Globe Staff / November 5, 2007

An international team led by a Boston researcher yesterday unveiled the most detailed look ever at the genetic ravages inside a lung tumor, finding at least one target for drug research and laying the foundation for an ambitious - and controversial - federal effort to identify all the DNA damage that causes major cancers.

The scientists found 57 genetic changes that commonly occur inside lung tumors, including a gene called NKX2-1 that gets duplicated again and again, indicating that it may be important to the growth of the disease.

Equally important, the researchers - including scientists from the Dana-Farber Cancer Institute and the Broad Institute of Harvard and the Massachusetts Institute of Technology - said their study validates a new ap proach to fighting the nation's number two killer: systematically identifying genetic changes that turn healthy cells cancerous, in hopes of finding cancer's weaknesses. The study serves as a pilot project for the federal government's proposed 10-year, $1.5 billion research program to map the genetic blueprint of the 50 most lethal cancers.

"You ain't seen nothin' yet," said Dr. Matthew Meyerson of Dana-Farber and the Broad who is the lead author of the paper posted online yesterday by the science journal Nature. "The potential for finding things that will help cancer patients is so great. This absolutely gives me much more confidence that we should go forward" with similar research in other types of cancer.

But the larger Cancer Genome Atlas project has been criticized by some researchers who fear that it will take too long and produce uncertain results, draining resources from more promising approaches to develop cancer treatments. There may be thousands of genetic defects associated with cancer, they say, and no easy way to tell which ones matter most - even with the NKX2-1 gene, researchers don't know what role, if any, it plays in cancer. As a result, critics say, researchers could spend millions to fill their zip drives with genetic information but not end up with new medicines.

"The miracle target ain't there or it doesn't appear to be," said Garth Anderson, a geneticist at Roswell Park Cancer Institute in Buffalo, adding that Meyerson's paper found genetic damage scattered across two-thirds of the DNA in lung tumor cells. Anyone hoping to find the tumor's primary weak spot amid so much genetic damage, he said, is "praying to a God that doesn't exist."

However, the driving force behind the cancer-mapping project, Dr. Francis S. Collins, said he was impressed at what Meyerson and the 69 coauthors from 26 institutions had found, pointing out that, in all the years of studying lung tumors, scientists never suspected that NKX2-1, a powerful gene that shapes the lining of air sacs inside the lungs, played a role. He also said that researchers have already succeeded in turning a previous genetic discovery into a cancer drug, Gleevec, which has been effective against a rare form of leukemia.

The new study "is a very encouraging early example of how applying such powerful tools can teach us things about cancer that we would never have discovered otherwise," said Collins, who had directed the $3 billion Human Genome Project that identified the roughly 25,000 genes necessary to create a human being. "It does give a real sense of increased momentum and excitement."

The controversy over the cancer atlas reflects the ambiguous results so far in the war on cancer, which is expected to kill 560,000 Americans in 2007 despite a research push that has cost the federal government alone $69 billion since 1971. People are less likely to die from cancer today, but that has more to do with early detection of the disease and changes in lifestyle such as the reduction in smoking rather than breakthrough medicines. Many of the most heralded new cancer drugs are very expensive and typically add only a few months to patients' lives, drawing increasing criticism from patient advocacy groups.

Now, with federal funding for cancer research nearly frozen at 2003 levels, many researchers are eager to funnel investment into areas that are likely to lead to better medicines more quickly. Even the main backers of the Cancer Genome Atlas say it is more likely to benefit today's children or even the next generation than any of the millions of current cancer patients.

"We need to be able to look cancer patients and their families in the eye and say, 'We are spending your money in the best way we know to find a cure for you,' " said Harvard Medical School geneticists Stephen J. Elledge and Gregory J. Hannon in a letter to the journal Science questioning the wisdom of the Cancer Genome Atlas in October 2005. In an interview last week, Elledge said he has the same reservations now.

Elledge said he strongly supports Meyerson's study, which cost a modest $1 million, but he said that it does not justify the costly, open-ended work that would be part of the larger blueprint program. He pointed out that Meyerson and his coauthors were looking for the easiest-to-find genetic defects, instances where normal genes either disappear or multiply. The majority of genetic defects in cancer cells involve more intricate damage that requires more lab analysis and much more money to spot.

"This is the least controversial part," said Elledge, who is a friend of Meyerson though not involved with the research.

The study, whose coauthors include prominent scientists such as Eric Lander of the Broad Institute and Nobel Prize recipient Harold Varmus of Memorial Sloan-Kettering Cancer Center in New York, reflects the growing understanding that cancer is caused by genetic damage to cells that builds up over a lifetime. Though some people are born with genetic defects that make them more vulnerable to certain cancers, scientists believe that the genetic damage from foods, environmental toxins, sun exposure, and other sources are far more important. In lung cancer, cigarette smoking causes much of the damage, eventually mutating normal cells into tumors that can grow without limit.

Before the Human Genome Project, which developed computing and lab tools for large-scale genetics, it would have been impossible to decode the blueprint for cancer. Cancer Atlas backers estimate that they may ultimately need to look at 10,000 times as much cancer DNA as the human genome decoders required. Lander explained that cancers are the product of a cascade of genetic defects that make each tumor unique.

"Happy families are all the same. Unhappy families are each unhappy in their own way," he said, quoting Tolstoy's "Anna Karenina."

To compensate for cancer's genetic variability, Lander and the other researchers collected samples of 371 lung adenocarcinomas - the most common form of lung cancer - and looked for genetic defects that occurred repeatedly. The excess copies of NKX2-1 was the single most common abnormality the team found, occurring in 12 percent of the tumors. Over all, Meyerson said he believes the team has identified less than half the genes involved in lung adenocarcinoma, and the team has already begun a second $8 million phase - paid for by Collins's institute - to identify the more subtle genetic defects through a labor-intensive process called gene-sequencing.

Though the study does not solve what Australian geneticist George Gabor Miklos calls the "needle in a haystack problem" - finding the most important cancer genes - Lander said he was encouraged that the team found a manageable number of defects, 57, to explore further. If even one turns out to be medically significant, he said, it could one day lead to a life-extending medicine.

The study, Lander said, "represents a general approach that can and should be used to analyze all types of cancer." Collins said the Human Genome Research Institute along with the National Cancer Institute will decide whether to go forward with the full-scale project at the conclusion of another study mapping genetic defects found in forms of brain, ovarian, and lung cancer.

Scott Allen can be reached at allen@globe.com.

(Correction: Because of a reporting error, a Page One story yesterday about cancer research gave a wrong author for the Russian novel "Anna Karenina." It was written by Leo Tolstoy.)

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