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RESEARCHERS SAY HEREDITY PLAYS A KEY ROLE IN LUNG CANCER

The Boston Globe - Wednesday , August 1, 1990 by Judy Foreman (Globe Staff)

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The National Cancer Institute announced yesterday that, contrary to widespread belief, heredity seems to have a strong influence on whether, and when, a smoker POSTs lung cancer.

For years, the evidence showing that smoking causes lung cancer was so clear that few researchers even bothered to wonder whether heredity might be involved as well.

But now, two new studies taken toPOSTher provide "the first strong evidence for gene- environment-lifestyle interactions" in causing lung cancer; according to an editorial accompanying the studies in this week's Journal of the National Cancer Institute.

"We wanted to know why some heavy smokers never POST lung cancer while others who seldom smoke or smoke not at all succumb to the disease. Now we know that inherited traits, similar to those that determine hair or eye color, play a vital rule in determining an individual's risk for cigarette-induced lung cancer," the institute said in releasing its findings.

One study, headed by Dr. Neil E. Caporaso, a physician and researcher at the National Cancer Institute, found that people who have two copies of a particular gene are at six times greater risk of developing lung cancer than people with just one copy or no copies of this gene.

About 90 percent of the population has either one or two copies of the gene, which is located on chromosome 22, Caporaso said in a telephone interview.

The gene makes an enzyme that metabolizes or chews up certain chemicals, including a drug called debrisoquine, which is used in Great Britain and Canada to treat high blood pressure. (Debrisoquine is not used in the United States because, among people genetically sensitive to it, it causes too sudden a drop in blood pressure.)

People with the gene for this debrisoquine-chewing enzyme metabolize debrisoquine quickly, while those without the gene metabolize it slowly.

This same enzyme, Caporaso said, probably also activates one or more carcinogens in cigarette smoke, though no one knows specifically which of several hundred carcinogens it may act on. Alternatively, the debrisoquine gene may actually be a marker for another gene nearby on chromosome 22 that plays the central role in activating tobacco carcinogens.

A person with no copies of this gene theoretically would have little lung cancer risk, though Caporaso was quick to add that regardless of the cancer risk, smoking is still dangerous because it also causes heart disease and stroke.

The link between the ability to metabolize debrisoquine quickly and lung cancer was first proposed by British researchers in 1984 in the journal Nature. But until this National Cancer Institute study, attempts to confirm the British findings had failed.

The other new study shows that possession of both copies of a theoretical lung cancer gene, possibly the gene that Caporaso studied, causes a smoker to develop lung cancer 45 years earlier than he otherwise might have.

Led by Thomas A. Sellers, assistant professor of epidemiology at the School of Public Health at the University of Minnesota, the researchers conducted a statistical study of 337 white families in southern Louisiana with histories of lung cancer.

While this team has not isolated the gene involved, they did trace lung cancer cases through at least three generations in each family. They found that the age of onset of the cancer seemed to follow a common pattern of inheritance, strongly suggesting that a gene is involved.

"In general, the earlier forms of a disease tend to have a genetic basis. That's the dogma, and this fits with that dogma," said Sellers in a telephone interview.

Sellers' group studied lung cancer cases according to the age of onset. They found that among people who got lung cancer at age 50, 27 percent of the lung cancers were attributable to the gene alone, 42 percent to the joint effect of the gene and smoking, 27 percent to smoking alone and 4 percent to neither the gene nor smoking.

For people who got lung cancer at age 70, only 9 percent of the lung cancers were attributed to the gene, 13 percent to the joint effect of the gene and smoking, 72 percent to smoking alone and 6 percent to neither smoking nor genetics.

This strongly suggests, Sellers said, that a gene "accounts for a large percent of the early cases. The gene alone does not cause lung cancer, but only does so with smoking or some other environmental insult."

Taken toPOSTher, the new studies may help explain why not all smokers develop lung cancer. Overall, only about 20 percent of smokers develop lung cancer.

Caporaso said: "The more you smoke, the more likely you are to POST lung cancer. But for any given individual, it's a crapshoot, your chances are one in five. And what determines that is something genetic, not the level of exposure."

George E. Bonney, in the editorial accompanying both articles, wrote that it is "a good hypothesis to begin with" that' the gene Caporaso studied and the putative gene Sellers infers as the hereditary link to cancer are the same.

Proving that only one gene is involved and that it acts on cigarette smoke the way Caporaso said it does "will take time, but the public health implications are obviously critical, and clues provided by the two studies are excellent and the analytical methods are available," Bonney said.

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