Weizmann Scientists Herald Discovery of Lung Cancer Marker

Researchers at the Weizmann Institute of Science have discovered a non-hereditary genetic risk factor that influences the tendency of tobacco smokers to develop lung cancer. The researchers have found that the chances of smokers with the genetic risk factor for lung cancer to develop the disease are 120 times greater than non-smokers who do not carry the genetic factor.

The genetic material is found in cell nuclei that are struck some 20,000 times a day by various forms of radiation such as solar radiation, come into contact with various materials such as cigarette smoke, and suffer internal damage caused by by-products of the body's metabolism. These are likely to upset the order of the elements that make up the genetic material and to create genetic mutations, which can lead to various diseases, particularly cancer.

To avoid the creation of such undesirable mutations, the cells activate enzyme systems that repair the damage caused to the genetic material. These systems scan the DNA and identify flaws using a sophisticated system of molecular sensors. When the system identifies a flaw, it conducts a kind of local surgery: The repairing enzymes cut and remove the affected areas and replace them with new, repaired DNA.

"The more efficient the repairing enzymes, the less the risk of mutations leading to cancer," says Prof. Zvi Livneh, head of chemical biology at the Weizmann Institute who conducted the research with Dr. Tamar Paz-Elizur. Also participating in the research were Dr. Meir Krupsky from Sheba Medical Center and other researchers.

Tobacco smoke contains several dozen carcinogenic elements that affect genetic composition. Most of the population manages to overcome the influence of those carcinogenic materials through defensive mechanisms like the repair mechanism.

"Statistics show that only 10 percent of `heavy' smokers develop lung cancer," says Livneh. "We asked ourselves what are the differences between smokers, and reached the conclusion that some are more sensitive or have a genetic predisposition. Our research shows that one of the reasons for the varying degrees of sensitivity is connected to a low level of one of the repairing enzymes."

The researchers focused on repairing enzyme OGG1, 8-oxoguanine DNA glycosylase 1. The enzyme functions to remove from the genetic material damage caused as a a result of oxidized radicals that are also found in tobacco smoke and that cause a large number of mutations. The researchers developed a new blood test, which enables measurement of the extent of OGG1 activity, and found that 40 percent of those people afflicted with lung cancer are characterized by a low level of that enzyme activity. In the healthy population, on the other hand, only 4 percent are characterized by low enzyme activity.

The researchers found that a person with low OGG1 is 5-10 times more likely to develop lung cancer than a person with a normal level of OGG1; and when a smoker has low OGG1, their relative chances of getting lung cancer are 120 times greater than the chances of someone with normal levels of OGG1 activity.

"That's very logical," says Livneh. "A person whose natural repair mechanisms are weak is more exposed to the damage caused to the genetic makeup since the repairing system is not capable of handling the burden. As a result, a large number of mutations form and the risk of lung cancer increases."

Livneh said that although only a minority of smokers have low levels of OGG1 activity, that is still many - some 160,000 such people fall ill every year in the U.S. alone. He said the research had several ramifications.

"Anti-smoking campaigns are not very effective in most cases because it is a general warning and people say, `It won't happen to me.' Now, if a person has a test and discovers they are in a high risk group, they will regard it as a personal message and it might give them motivation to quit smoking."

Livneh added that his team was now working on the development of a simpler, cheap way for health organizations worldwide to offer blood tests that would provide information about the risk level of someone being examined.

"It takes us three days to get results in the labs. The goal is to make the test simple. In addition, we'll examine the connection between this enzyme and others that are responsible for other forms of cancer."