Zvi Livneh

Ph.D.

Weizmann Institute of Science

Professor. Head of the Swiss Society Institute for Cancer Prevention Research at WIS

PLCO (Learn more about this study)

2021-0018

Jun 14, 2021

Prospective study of DNA repair functional assays and risk of lung cancer

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.