Analysis of the predictability of lung cancer using DNA Repair functional assays and cryopreserved blood samples of the PLCO prospective cohort

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Project Summary/Abstract Elucidating the etiology of lung cancer is interwoven with the identification of risk factors for the disease, and is critical to advance prevention, and assist early detection of this lethal tumor. While smoking status and aging are well documented key lung cancer risk factors, along with several additional risk factors including certain environmental and occupational carcinogenic exposures, there is a gap in our knowledge of other important causes of the disease including biological processes that may modify the impact of exposures or be independent risk factors. Because DNA repair ability is key in avoiding mutations and preventing cancer, and likely reflects multiple inherited and other influences, we have previously developed a panel of three functional DNA repair blood tests, which directly measure an individual’s effectiveness at repairing oxidative DNA damage by the enzymes OGG1, MPG and APE1. Using these tests in a case- control study, we found that a low DNA repair score, calculated from the three tests, was strongly associated with lung cancer in addition to and independent of smoking. This was recently replicated in a second case-control study, suggesting that adding the DNA repair score to current lung cancer risk models is likely to substantially improve risk prediction. The data so far is consistent with a causative role in lung cancer, but because the findings are based on case-control studies, where disease bias cannot be ruled out, persuasive evidence to support a role of a low DNA repair score in lung cancer etiology requires demonstrating its ability to predict lung cancer in prospective cohort studies. Our goal is to examine the predictive ability of the DNA repair score for lung cancer in a nested case- control study within a prospective cohort, namely the PLCO Screening Trial. DNA repair activity will be measured in expanded T cells from PLCO pre-diagnostic cryopreserved viable whole blood samples of current smokers and never-smokers who subsequently developed lung cancer, and will be compared to samples from matched controls who did not develop any type of cancer, from which the ability to predict lung cancer can be inferred. Further, DNA repair tests will be expanded with three new functional tests for the DNA repair enzymes TDG, SMUG1 and NEIL1. Using a set of test samples received from the PLCO Trial, we have demonstrated that T cells could be effectively and efficiently expanded from whole blood samples cryopreserved for 12 or 20 years, and were suitable for measuring all six DNA repair enzyme activities, yielding reproducible values comparable to fresh lymphocytes. A successful outcome of this study will support the role of sub-optimal DNA repair of oxidative DNA damage in the etiology of lung cancer, and will facilitate the adaptation of the DNA repair score into clinically-validated biomarkers for risk assessment of lung cancer. This is expected to improve risk estimates, and provide better selection criteria for early detection of lung cancer by methods such as low-dose CT. 1