A new blood test reveals that the relative risk of smokers whose genetic baggage includes the new risk factor, of developing lung cancer, is 120 times greater than the risk of regular non-smokers
A group of scientists from the Weizmann Institute of Science, led by the head of the Department of Biological Chemistry, Prof. Zvi Livna, and Dr. Tamar Paz-Elitzur, from the same department, recently discovered a new genetic risk factor that affects the tendency of smokers to develop lung cancer. The relative risk of smokers whose genetic load includes the new risk factor, of getting lung cancer is 120 times greater compared to the risk of non-smokers who do not carry the discovered risk factor in their genetic load. The findings of this study, which are published today in the scientific journal Journal of the National Cancer Institute (JNCI), may serve as a basis for the development of a test kit that will make it possible to diagnose the smokers who are in the particularly high risk group. The research was carried out in collaboration with Dr. Meir Krupsky from the Sheba Sheba Medical Center in Tel Hashomer.
The discovery is based on multi-year research carried out by Prof. Livna and the members of his research group, with the aim of understanding the mechanisms that repair the damage that is constantly occurring in the genetic material, DNA. The genetic material stored in the cell nuclei in our body is damaged about 20,000 times every day. These are injuries that are caused, for example, as a result of absorbing radiation, such as the sun's radiation, as a result of contact with various substances such as cigarette smoke, and as a result of the damage of internal factors that are created as byproducts of the body's metabolism. These injuries may disrupt the order of the components of the genetic material and create genetic mutations (transformations), which may lead to the development of various disorders and diseases, especially cancer.
To avoid the formation of unwanted mutations, the cells activate enzyme systems to repair the damage that is constantly caused to the genetic material. These systems scan the DNA, and locate defects in it using a sophisticated system of molecular sensors. When the system detects damage, it performs a kind of local analysis on the DNA: the repair enzymes cut and remove the damaged area, and replace it with a new DNA segment, similar to removing a damaged component in a computer, and replacing it with a new component. The efficiency of the DNA damage repair systems is of central importance in cancer prevention: effective detection and repair will prevent mutations, and reduce the risk of cancer, while a defect in damage repair will cause an accumulation of mutations, and a high risk of cancer. Indeed, the cause of some hereditary cancers (which occur with high frequency in certain families) is a hereditary genetic defect in one of the components of the DNA damage repair system. Among these cancers we can mention hereditary bowel cancer and hereditary breast cancer.
The vast majority of cancers are not hereditary. In the current study, Prof. Livna tried to check whether a low personal (non-hereditary) ability to repair DNA damage increases the risk of developing cancer. The researchers chose to focus on lung cancer. It is one of the most common types of cancer in the world, and one of the deadliest, responsible for 30% of cancer deaths. A major factor in the morbidity of this cancerous disease is smoking, a habit that is known to be difficult to quit. More statistics show that about 90% of the lung cancer patients admitted to the hospitals are smokers. However, when you examine all smokers in the population, only 2.5% of them develop cancer, and among the "heavy" smokers the rate of developing cancer does not exceed 10%. This finding shows that most people manage to overcome the effect of the carcinogens found in tobacco smoke through defense mechanisms which work in their bodies, such as the DNA repair mechanisms. But on the other hand, a relative minority (in absolute numbers, this is a very large number of people) has an excessive genetic sensitivity to the harmful effect of tobacco smoke, and is therefore at a very high risk of lung cancer. In the USA, this relative minority numbers about 160,000 new patients every year.
Tobacco smoke includes dozens of carcinogenic substances that damage DNA, which the body needs to defend against. For this, the cells in the human body are helped by a long series of enzymes that repair the damaged DNA. The researchers set out to find out whether a reduced ability to repair DNA damage is a personal genetic risk factor for lung cancer. They chose to focus on a particular repair enzyme, called OGG1 for short (and its full name: 1-oxoguanine DNA glycosylase 8; 1-oxoguanine DNA glycosylase 8). This repair enzyme removes from the DNA damage caused by the formation of oxygen radicals that are also found in tobacco smoke (this is damage that causes mutations at a high rate). The researchers developed a new blood test, which allows to measure the degree of activity of the OGG1 enzyme. Using this method, the researchers found that approximately 1% of lung cancer patients are characterized by a low level of activity of OGG40, while among the healthy population, only 1% are characterized by a low level of activity of this enzyme.
These and other findings show that a person with weak OGG1 activity has a relative risk of developing lung cancer 5-10 times greater than a person with normal OGG1 activity. As we know, smoking increases the risk of lung cancer. When a smoker has low OGG1 activity, his relative risk of developing lung cancer is 120 times greater than the risk of a non-smoker whose OGG1 activity is normal. This is probably because a person with low OGG1 activity has difficulty dealing with DNA damage. Tobacco smoke causes a large accumulation of DNA damage, and then, its weak repair system cannot withstand the load, and as a result, the number of mutations greatly increases, and the risk of lung cancer increases greatly. This finding may help in diagnosing people who smoke (including "passive smokers") who are at a particularly high risk of getting lung cancer. Stopping smoking (or preventing exposure to smoke) of those people may greatly reduce the level of risk that they will get lung cancer.
The scientists say that this finding raises the possibility of finding personal (non-hereditary) genetic risk factors for contracting additional cancers.
Prof. Livna's research team in the Department of Biological Chemistry at the Weizmann Institute of Science also included (then) post-doctoral researcher Dr. Sarah Blumstein, and Dalia Ellinger. The statistical analyzes were performed by Dr. Edna Shechtman from Ben-Gurion University of the Negev.
