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Principal Investigator
Name
Zvi Livneh
Degrees
Ph.D.
Institution
Weizmann Institute of Science
Position Title
Professor. Head of the Swiss Society Institute for Cancer Prevention Research at WIS
Email
About this CDAS Project
Study
PLCO (Learn more about this study)
Project ID
2021-0018
Initial CDAS Request Approval
Jun 14, 2021
Title
Prospective study of DNA repair functional assays and risk of lung cancer
Summary
Effective early detection, which dramatically increases lung cancer 5-year survival rate, is facilitated by risk factors, which for lung cancer are mainly age and smoking-history. Because DNA repair is crucial for avoiding mutations, sub-optimal DNA repair is likely to cause cancer risk. Using functional DNA repair enzyme blood tests that we developed, we previously conducted, with NIH/NCI/EDRN support, a blinded population-based case-control study with 96 lung cancer patients and 96 controls matched by gender, age (±1year), residence, and ethnicity. We found that a low DNA Repair Score, calculated from the DNA repair enzymatic activities of OGG1, MPG and APE1, is strongly associated with increased lung cancer risk, with estimated relative risk of 9.7, 95%CI=3.1–29.8; P<0.001. This personal DNA repair biomarker is independent of and additional to the risk caused by smoking. Recently this result was replicated with newly diagnosed lung cancer patients in an independent case-control study in the UK, in collaboration with Cambridge University and Papworth Hospital, yielding an OR=7.2, 95%CI=3.0-17.5, P<0.001. Initial calculations suggest an AUC=0.89 when combined with age/smoking, and 0.81 for DNA Repair Score alone. We have recently developed three new blood tests for the DNA repair enzymes TDG, SMUG1 and NEIL1, broadening the DNA repair scope, and adding an epigenetics component, since TDG, and SMUG1 are involved in 5-methylcytosine demethylation. This may allow to expand the risk panel to 4-6 DNA repair enzymes.
While our retrospective studies provided strong evidence for association of low DNA repair with lung cancer, our current goal is to examine whether low DNA repair is predictive of lung cancer, using cryopreserved blood from the PLCO trial. Towards this goal we propose a nested case-control study, with frozen viable blood samples from cases and matched controls. Specifically, we propose to examine whether DNA repair activity measured in the expanded T cells from cryopreserved whole blood, is predictive of the appearance of lung cancer 2+ years later. To that end we have established in our lab a protocol for ex-vivo expansion of T cells from cryopreserved PBMC or whole blood, and automated it. To test the feasibility of using PLCO samples for enzymatic DNA repair testing, we have requested, and received from NCI healthy donor samples that were cryopreserved in 2009 according to the PLCO protocol, and T3 samples from 5 subjects in the PLCO Trial (from 2000-2003) who were eventually excluded. Remarkably, all 17 samples tested (14 from 2011 and 3 from 2000-2001) grew successfully, yielding tens of millions of T cells, with >90% viability, and with DNA repair enzyme activity typical of T cells expanded from freshly drawn blood. These results provide an indication that most of PLCO samples requested will likely grow, and enable us to tests the predictability of the DNA repair biomarkers. A successful outcome of this study will facilitate implementation of the DNA repair biomarkers in risk assessment of lung cancer, which is expected to enable better early detection of lung cancer by methods such as low-dose CT.
Aims

The case-control studies that we have conducted demonstrated a strong association of low DNA Repair Score with lung cancer, indicating that sub-optimal DNA repair is a risk factor for, and may be predictive of lung cancer. Importantly, low DNA repair score is a risk factor which is independent of and additional to smoking status, suggesting that it is a risk factor also in never smokers. Several lines of evidence suggest that sub-optimal DNA repair plays a causative role in lung cancer (Cancer Prevention Res. 7, 398-406, 2013; J. Natl. Cancer Inst. Cancer Spectrum, 2020, 4(1): pkz067 doi: 10.1093/jncics/pkz067). Yet persuasive evidence requires to demonstrate that the the DNA Repair Score that we have developed can predict the development of lung cancer. Towards this goal we propose a nested case-control study, with frozen viable blood samples from cases and matched controls. Because smoking is a major lung cancer risk factor, we propose to match for smoking status, to minimize a potential confounding effect. Hence, we propose two case-control arms: one for smokers and the other for never-smokers.
Our specific aims are as follows:
1. Examine whether DNA repair activity measured in the expanded T cells from blood of smokers, is predictive of the appearance of lung cancer 2+ years later. This will be done in a nested case-control study of PLCO samples, including 150 T3/T5 blood samples of smokers with non-small cell lung cancer cases (75 with adenocarcinoma and 75 with squamous cell carcinoma), and 150 T3/T5 blood samples of matched control smokers, who were alive and with no diagnosis of any type of cancer at the time their matched case was diagnosed.
2. Examine whether DNA repair activity measured in the expanded T cells from blood of never-smokers, is predictive of the appearance of lung cancer 2+ years later. This will be done in a nested case-control study of PLCO samples, including 87 T3/T5 blood samples of never-smokers with lung cancer (all available types of histology), and 87 T3/T5 blood samples of matched control never-smokers who were alive and with no diagnosis of any type of cancer at the time their matched case was diagnosed.
3. Based on the results obtained in objectives 1 and 2 we shall examine whether smoking status affects the levels of DNA repair activity, and whether smoking status modifies the association between specific DNA repair markers and lung cancer.

Collaborators

Zvi Livneh (Weizmann Institute of Science)
Tamar Paz-Elizur (Weizmann Institute of Science)
Nathaniel Rothman (DCEG, NCI, NIH)
Qing Lan (DCEG, NCI. NIH)
Noya Galai (Johns Hopkins University (USA) and Haifa University (Israel))