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Some 85% of smokers never get lung cancer, while a small percentage of unlucky non-smokers fall prey to the disease. Smoking is, of course, still the main known risk factor, but a test for susceptibility to this cancer could help prevent many deaths. Recent Weizmann Institute research suggests that a combined test for three different biological markers provides a “DNA repair score” revealing an individual’s odds of developing lung cancer.
Prof. Zvi Livneh and Dr. Tamar Paz-Elizur of the Biological Chemistry Department have been investigating such markers – biological molecules that are over- or under-active – for the past several years. Their research has focused on the DNA repair mechanisms in the cells for mending the damage caused, among other things, by the harmful substances in tobacco smoke. The assumption is that even small deficiencies in these repair mechanisms could allow cancer processes to begin. Indeed, the team found one such molecule, an enzyme called OGG1, whose activity is strongly associated with lung cancer: Very low levels of OGG1 activity increased the risk of this cancer fivefold.
Although checking for OGG1, alone, could give a good indication of cancer risk, Livneh and his team continued searching for further DNA repair mechanisms in hopes of improving the test and narrowing the margin of error. Around a year ago, they discovered a second factor, called MPG, which is linked to the tendency to develop lung cancer. Surprisingly, it was high levels of MPG activity, rather than low ones, which were associated with increased risk. The researchers think that a balance between OGG1, MPG and other DNA repair enzymes is critical; imbalances between them may lead to inefficient repair efforts.
Now, in a study that was recently published in Cancer Prevention Research, Livneh, Paz-Elizur and Drs. Ziv Sevilya and Yael Leitner-Dagan, and Dalia Elinger; in collaboration with Prof. Gad Rennert, Dr. Mila Pinchev and Hedy Rennert of the Technion School of Medicine and Carmel Medical Center; Dr. Ran Kremer of Rambam Medical Center; Prof. Laurence Freedman of Sheba Medical Center; and Prof. Edna Schechtman of Ben-Gurion University of the Negev, have found that a third DNA repair enzyme, called APE1, is also strongly tied to lung cancer risk. Higher risk came with reduced APE1 activity, although, interestingly enough, it has been known to be overexpressed in certain established cancers. The scientists think that APE1 may play a dual role in cancer: In healthy cells it acts weakly, allowing the accumulation of mutations that can speed up the development of cancer; while in cells that have already become cancerous, increased APE1 activity grants an advantage, enabling faster DNA replication and proliferation.
The researchers developed a method of weighting the levels of all three biomolecules in the form of a “DNA repair score,” along with the history of smoking, to determine the total risk. Checking these factors in 100 lung cancer patients and comparing them with those of healthy people, they found that people with a low DNA repair score have a 10-20-fold increase in their risk of getting lung cancer. While larger-scale clinical trials are needed to confirm the efficacy of the so-called OMA (OGG1-MPG-APE1) DNA repair score – a personalized measure of DNA repair activity – Livneh is optimistic that it will become a powerful tool for assessing cancer risk and directing individuals at risk to seek early detection though proactive CT scans. In addition, a study is planned to search for novel drugs that will improve DNA repair as a strategy to reduce the risk of lung cancer and perhaps other types of cancer.
Prof. Zvi Livneh’s research is supported by the Y. Leon Benoziyo Institute for Molecular Medicine, which he heads; the Leona M. and Harry B. Helmsley Charitable Trust; the David M. Polen Charitable Trust; Dana and Yossie Hollander, Israel; Mike and Valeria Rosenbloom through the Mike Rosenbloom Foundation; and the Sergio Lombroso Award for Cancer Research. Prof. Livneh is the incumbent of the Maxwell Ellis Professorial Chair of Biomedical Research.
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