added risk

Locating risk factors for diseases and their early diagnosis, even before their outbreak, are the most effective ways to fight them. The earlier the detection, the greater the chance of prevention and cure. Thus, for example, a considerable part of the steep decline in heart disease can be attributed

Locating risk factors for diseases and their early diagnosis, even before their outbreak, are the most effective ways to fight them. The earlier the detection, the greater the chance of prevention and cure. Thus, for example, a significant part of the steep decline in heart disease in recent decades can be attributed to the discovery of a major risk factor - high blood cholesterol levels - and its treatment. On the other hand, when it comes to cancer, the situation is much less encouraging. Discovering biological markers that indicate an increased risk of developing cancer is a challenge that occupies many groups of scientists around the world.

The research of Prof. Zvi Livna and Dr. Tamar Paz-Elitzur, from the department of biological chemistry at the institute, focuses on genetic markers of a certain type: they examine the set of tiny cellular "machines", whose job it is to maintain the integrity of the genetic material. The DNA stored in the nuclei of all the cells in our bodies is damaged thousands of times every day, as a result of radiation, by-products of the body's metabolism, and various harmful substances. These injuries may cause disruptions in the DNA sequence (mutations), which may cause various diseases - including cancer. To avoid the formation of harmful mutations, the cells activate an array of molecular machines, whose role is to locate damages caused to the genetic material in the cell, and repair them. "Our working assumption is that small differences between people in the ability to repair DNA affect the degree of risk of developing cancer," says Prof. Livna. "The combination of two factors - exposure to a risk factor, together with a low ability to repair the DNA, increases the tendency to develop the disease."

About a decade ago, Prof. Livna and Dr. Paz-Elitzur were able to prove this assumption, when they discovered a biological marker that indicates an increased risk of developing lung cancer. It is one of the most common types of cancer in the world, and the deadliest of them: it is responsible for about 30% of cancer deaths. Every year 160,000 people die from it in the US, and 220,000 new patients are added. The main risk factor for lung cancer is smoking, but the data show that "only" 15-10% of all heavy smokers develop it, and that about 15% of lung cancer patients do not smoke. The meaning of the data is that most people manage to overcome the damage that cigarette smoke causes to DNA (although, it may still cause other diseases), but a minority of them suffer from an increased genetic sensitivity to smoke, which greatly increases the risk of contracting the disease. Prof. Livna and Dr. Paz-Elitzur succeeded in developing an accurate method for measuring the activity of one of the repair machines, an enzyme called OGG1, and discovered that the increased sensitivity is related to reduced activity of the enzyme: reduced activity of OGG1 increased the risk of developing lung cancer fivefold, and there is more to this Add the "extra risk" caused by smoking.

In the current study, Prof. Livna, Dr. Paz-Elitzur and Dr. Yael Leitner-Dagan sought to expand the scope, and reach a higher level of accuracy in predicting the risk of lung cancer. To this end, they developed a method to measure the activity of another repair machine, called MPG. This enzyme, like OGG1, also treats oxidative damage, but it covers a wider range of damage - such as, for example, those caused by chemotherapy treatment. In collaboration with Prof. Gad Rennert from the Technion and the "Carmel" Medical Center, and Dr. Ran Kramer from the Rambam Medical Center, the scientists collected blood samples from 100 lung cancer patients, and from 100 healthy subjects, who served as a control group, and tested the level of activity in them The MPG enzyme. The experiment was done blindly, and the sick subjects were matched to the control subjects in terms of age, sex, and area of ​​residence - to neutralize possible bias factors.

The scientists discovered that there is indeed a correlation between the degree of activity of MPG and the tendency to get lung cancer, but to their surprise it was the opposite correlation than expected: in lung cancer patients an increased activity of the enzyme was actually discovered. How do you explain the data? "MPG works on a wide range of damages, but it has a price: it doesn't always succeed in cutting out the damaged part of the DNA," explains Prof. Livna. "In such cases, it gets 'stuck' on top of the DNA, preventing access to repair enzymes that are able to carry out the repair. That is, at levels that are too high, MPG is more harmful than helpful." When the scientists calculated a weighted score, based on the activity of the two enzymes, they were able to predict with a higher degree of accuracy the tendency to get lung cancer. The research findings were recently published in the scientific journal Journal of the National Cancer Institute.

The scientists hope that, based on the method for measuring the activity of the machines that repair DNA damage, it will be possible in the future to develop methods to repair damaged machines, and to regulate their activity, thus preventing increased susceptibility to cancer. Since some machines are overactive, while other machines are underactive, a drug cocktail may be needed for precise regulation of each individual machine. Another possibility is that there is a common "superior" control factor for all machines, whose correction will bring the whole system back to balance. Prof. Livna and his staff plan to test these possibilities using the advanced equipment that will be available to them at the National Institute for Personalized Medicine, which was recently inaugurated at the institute.

Dr. Ziv Sevilla and Delia Ellinger, from Prof. Livna's group, and Dr. Mila Pinchev and Hedi Rennert from Prof. Rennert's group also participated in the study. The statistical analyzes were conducted by Prof. Lawrence Friedman from the Gartner Institute for Epidemiology and Health Policy Research in Tel Hashomer, and Prof. Edna Shechtman from Ben Gurion University of the Negev.