DNA’s smoking gun

Most cases of lung cancer—the leading cause of cancer death—are caused by smoking. That puts heavy smokers first in line for medical screening procedures that seek to identify lung tumors early, so that patients can begin treatment and improve their chances for long-term survival.

Today, screening protocols are based on identifying individuals considered likely to develop lung cancer, based on their age and smoking status. However, reliance on these two risk factors alone isn’t enough, as preventative screening in this selected population misses most lung tumors. Moreover, individuals who are not obvious candidates for screening remain unaware of the danger they may face—leading to delayed treatment and poorer prognosis.

Now, scientists at the Weizmann Institute and colleagues in the UK have proposed a new lung cancer screening protocol based on a simple blood test. It relies on individual patients’ “DNA repair scores”— a summation of the activity of three DNA repair enzymes through which cells are known to respond to genetic damage. Lower scores translate into heightened risk for lung cancer.

The study was led by Prof. Zvi Livneh and senior staff scientist Dr. Tamar Paz-Elizur, both members of the Weizmann Institute Department of Biomolecular Sciences, in collaboration with Prof. Sir Bruce Ponder of Cambridge University and Prof. Robert Rintoul from Royal Papworth Hospital and Cambridge University. The scientists’ findings were published in Journal of the National Cancer Institute-Cancer Spectrum (JNCI-CS).

In a study involving British patients, the scientists examined 150 individuals with non-small-cell lung cancer, as well as 143 healthy controls. They calculated each participant’s DNA repair score based on blood activity levels of three enzymes known to respond to DNA damage. The DNA repair score of study participants with lung cancer was lower than the control group across the board, establishing this enzymatic activity as a robust biomarker for lung cancer risk—independent of smoking. Importantly, these results validated a previous study by Prof. Livneh that examined DNA repair scores in an Israeli population, showing that the new approach could potentially be implemented to promote more effective lung cancer screening worldwide.

Together with his colleagues, Prof. Livneh demonstrated that a low DNA repair score reveals a five-fold greater risk for lung cancer onset than would typically be estimated based on age and smoking status alone. A low DNA repair score may also help explain why some non-smokers—normally not referred for preventative screening—develop lung cancer, thereby contributing to the development of clinical criteria for promoting early diagnosis in the non-smoking population. These findings have important implications for improving the effectiveness of lung cancer screening, and providing more at-risk patients with access to early diagnosis and treatment.

In another, unexpected finding that emerged from this study, Prof. Livneh’s team found that a low DNA repair score in lung cancer patients, but not in healthy people, correlates with a broad increase in gene expression pathways that mediate the body’s immune response. This indicates that DNA repair score data—as revealed in a blood test—could potentially contribute to personalized therapy, by helping doctors predict how individual lung cancer patients will respond to immunotherapy.

Prof. Livneh is supported by the Steven B. Rubenstein Research Fund for Leukemia and Other Blood Disorders, the Comisaroff Family Trust, Dana and Yossie Hollander, the Herbert L. Janowsky Lung Cancer Research Fund, the Gerald O. Mann Charitable Foundation,the  Pearl Welinsky Merlo Foundation Scientific Progress Research Fund, Rising Tide Foundation, Mike and Valeria Rosenbloom Foundation, and the Wagner-Braunsberg Family Foundation. He is head of the Swiss Society Institute for Cancer Prevention Research and is the incumbent of the Maxwell Ellis Professorial Chair of Biomedical Research.