Sunday, July 25, 2004

Lung cancer gene region identified

UC study paves way for screening test

By Tim Bonfield
Enquirer staff writer

University of Cincinnati genetic researchers Marshall Anderson and Susan Pinney have located a narrow region of genes that can sharply increase a person's risk of developing lung cancer.
Photos by MICHAEL E. KEATING/The Enquirer

Anderson displays noncancerous lung tissue, mounted in paraffin, that was used in the UC research. The study offers hope for better lung-cancer screening.
In a stunning medical breakthrough, researchers led by University of Cincinnati scientists have located a narrow region of genes that can sharply increase a person's risk of developing lung cancer - America's No. 1 cancer killer.

The discovery offers rare good news in the fight against a disease with abysmal survival rates. It paves the way for research and development of a genetic screening test for lung cancer and better medicines to treat or prevent the disease.

Those advances are still years away. But already, the researchers' work represents a major step in understanding why some people get lung cancer even if they never smoked. It also suggests that for people carrying a lung cancer gene, even a mild smoking habit or exposure to second-hand smoke can threaten their lives.

"This is a big development," said Janet Healy, executive director of the Alliance for Lung Cancer Advocacy Support and Education, based in Vancouver, Wash.

"So many people say that if we can just get people to stop smoking, all the questions about lung cancer would be answered. This study shows that there's more going on than we assumed."

The finding ranks among the top scientific advances to come out of UC.

Funded by the National Cancer Institute, the five-year, $5.9 million project involved a consortium of a dozen medical centers and top federal health agencies. The consortium was coordinated by UC researcher Dr. Marshall Anderson.

The full study has been posted on the Web site of the American Journal of Human Genetics and will be published in the journal's September edition.

The results come after a five-year nationwide hunt for genetic data from families that have suffered three, four, even as many as eight cases of lung cancer among blood relatives. The project started with more than 26,000 lung cancer patients, from whom researchers found 52 families that could be studied.

"When we started out, a lot of people didn't believe lung cancer would have this kind of gene. By finding these families, we have shown that it does," said Anderson, the study's principal investigator and UC professor of environmental health.

Few other common forms of cancer have so desperately needed some positive news.

This year, lung cancer will kill more than 160,000 people in the United States, including more than 14,600 in Ohio, Kentucky and Indiana. That's more than the next four leading causes of cancer death - colon, breast, pancreas and prostate - combined, according to the American Cancer Society.

Lung cancer also is one of the hardest cancers to beat.

The Genetic Epidemiology of Lung Cancer Consortium is still seeking families with multiple cases of lung cancer to participate in ongoing research. For information, contact the UC Family Lung Cancer Study at (513) 558-3120, 558-4028 or 558-0559. People also can check the project Web site or e-mail
Objective: To identify genes that make people more susceptible to lung cancer

Launch date: May 1999

Grant amount: $5.9 million, five-year grant from the National Cancer Institute to the Genetic Epidemiology of Lung Cancer Consortium.

Principal investigator: Dr. Marshall Anderson, University of Cincinnati and leader of the lung cancer consortium

Participating organizations: University of Cincinnati; the National Human Genome Research Institute, Baltimore; the National Cancer Institute; MD Anderson Cancer Center, Houston; Mayo Clinic, Rochester, Minn.; University of Colorado; Wayne State University Karmanos Cancer Institute, Detroit; Washington University, St. Louis; University of Texas Southwestern Medical Center; Louisiana State University Health Sciences Center; St. Mary's Hospital Saccomanno Research Institute, Grand Junction, Colo; and the Medical College of Ohio, Toledo.

Facts about lung cancer
While the overall five-year survival rate for breast cancer is nearly 87 percent, and the survival rate for prostate cancer is nearly 98 percent, fewer than 15 percent of people with lung cancer live so long.

"Unfortunately, the mortality rate for lung cancer hasn't changed very much since I started in medicine 25 years ago. Now we have an opportunity to make some meaningful clinical progress," said Dr. William Martin, dean of the UC College of Medicine, who has treated lung cancer patients during his career.

The findings

Anderson and co-investigator Dr. Susan Pinney, an epidemiologist with UC's department of environmental health, coordinated the work of more than 20 researchers scattered nationwide. The researchers' report concludes for the first time that families with multiple cases of lung cancer share an inherited genetic trait that can make it harder for their bodies to stop tumor growth. From the estimated 30,000 to 40,000 genes in the human body, researchers traced the common trait to an area of just 50 genes located along chromosome 6, one of the body's 22 pairs of chromosomes.

People carrying this trait would be especially vulnerable to the harm caused by smoking, and they could pass the trait on to their children, Anderson and Pinney said.

More work is needed to pin down the lung cancer gene itself, but the discovery so far is impressive to geneticists and cancer experts.

"Narrowing it down that much is the hardest first step," said Dr. Ranjan Deka, a geneticist at UC who is studying diabetes and obesity. "To identify even a region of genes in a disease as complex as lung cancer is a very challenging task."

UC officials say the research will help lung cancer patients and the institution.

"We're feeling very proud to be a part of this. It really showcases the kind of work we do," said Dr. Jane Henney, senior vice president and provost for health affairs at the UC Medical Center.

"People have known for a long time that tobacco smoke is a carcinogen, but there have been questions about why some people can smoke like chimneys and never develop lung cancer and some people can get lung cancer who have never smoked," Henney said. "There's something going on here genetically, and this is one big piece of evidence about where that genetic variation may be."

Benefit for relatives?

For people who have lung cancer now, these findings will have minimal effect on their chances of survival. It could take years - if ever - to develop new treatments.

But for the relatives of people with lung cancer, the discovery raises some potentially unsettling questions. It suggests, for example, that at least some of the brothers, sisters, sons and daughters of lung cancer victims were born with an increased risk of the disease.

No one knows yet how widely shared this genetic trait may be in the U.S. population. But even as this project progressed, three relatives in the study were found to have early-stage lung cancer and went on to begin treatment, Pinney and Anderson said.

If nothing else, news of a genetic link to lung cancer could help reduce some of the stigma people with lung cancer have faced for decades, says Healy, of the lung cancer advocacy group. That in turn could inspire more political support to spend money to improve treatment.

"It isn't just about smoking. For some people, getting lung cancer isn't their fault," Healy said. "A major factor in why lung cancer research hasn't gotten as much attention (as other types of cancer) is that we know what causes most cases: Smoking. And in so many ways, that's where the conversation seems to stop."

No one believes tobacco will be banned anytime soon. But even if all smoking could be banished today, lung cancer would remain a major cancer killer for the next 20 years, Anderson said.

"One of the reasons the (National Cancer Institute) funded this study is that they know they can't lower the national death rates from cancer much further without getting control of lung cancer," Anderson said.

Practical limits

Even after a genetic link to lung cancer is proven, such findings should not be misinterpreted, Anderson said.

It won't be safe for people to smoke if they don't have the gene. Most cases of lung cancer still trace to heavy smoking habits, Anderson said.

Many of the more than 6,000 patients referred to the study from Greater Cincinnati were sent by Dr. Richard Levy, a Greater Cincinnati radiation oncologist, and other partners in Oncology/Hematology Care Inc.

Levy said the study is clearly valuable to scientists.

"We need to better understand the molecular biology of lung cancer," he said. "You can't do gene therapy without identifying the gene."

In the short term, finding a gene linked to lung cancer won't change treatment for people who have the disease. "But it does change thoughts about early detection," Levy said.

Currently, some studies have reported that CT scans can detect smaller lung cancer tumors than other methods, such as chest X-rays or collecting sputum samples. Some people already pay hundreds of dollars to get such scans, even though many insurers won't cover the costs.

But it remains unclear whether CT scans detect lung cancer early enough for treatment to actually improve survival, said Dr. Rebecca Bechhold, an oncologist with Levy's group.

Doctors disagree over how widely such tests should be offered. Critics remain concerned about false positive results triggering unnecessary biopsy tests. But supporters say the tests may be especially appropriate for high-risk groups.

Beyond the CT scan debate, treatment and prevention options would be limited for people with a lung cancer gene.

For example, some women who have the BRCA-1 or BRCA-2 breast cancer genes have opted to have double mastectomies as a purely preventive measure.

In lung cancer, surgery to remove part of the lung remains the best hope of long-term survival. But performing such surgery as a preventive measure isn't realistic, Levy and Bechhold said.

For now, the way for a high-risk gene carrier to avoid lung cancer is to stop smoking -- something people should already know, Bechhold said.

"The bottom line is that people need to stop smoking. Period. Whether they have the gene or not," she said. "I already see patients all the time whose family members continue to smoke, even after they see what their family members go through. If watching a loved one die from lung cancer doesn't convince them to stop smoking, I can't see how knowing they had a genetic risk would make a difference."

Other experts take a more optimistic view.

Dr. John Wiest, a researcher with the National Cancer Institute and a co-author of the study, said finding new molecular targets has led to new treatments for other types of cancer. Now that's the hope for lung cancer.

"The potential for progress is there," he said. "The demonstration of genetic susceptibility in lung cancer will have an impact on the field."


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