EXACT · Identifying biomarkers of Exposure leading to Lung Cancer with Adductomics

Identifying biomarkers of Exposure leading to Lung Cancer with Adductomics

Lung Cancer (LC) is the leading cause of cancer death worldwide (1.8 million deaths in 2018), the survival of patients is highly depended on accurate and early diagnosis, and current methods are reported to partially result in diagnostic error resulting in treatment delay and decrease of survival rates. Further knowledge is needed to detect early markers of lung cancer and improve understanding of early carcinogenesis. Lung Cancer is known to be causally linked to tobacco smoke and recently air pollution has also been recognized as a lung carcinogen. To understand the mechanisms of LC onset, methods are needed to characterize specific toxicants in tobacco smoke and air pollution that people are exposed to, as well as molecular pathways. Electrophiles present in blood are highly reactive species that have been long suspected of causing cancer and other diseases. These electrophiles enter the organism by direct exposure (inhalation, ingestion) or via internal mechanisms such as metabolism of exogenous compounds, oxidation of lipids, and inflammation associated with prior disease and contribute to oxidative stress. Oxidative stress (OS) has been linked to smoking habits and is known to contribute to carcinogenesis. Reactive oxygen species (ROS) contribute to oxidative stress, causing cell damage, but as they are small and rapidly degraded, they cannot be easily quantified. These highly reactive species have been long suspected of causing cancer and other diseases because of their ability to bind to DNA and proteins. The challenge for their measurement is due to their very short half-life in the body and their high reactivity, which makes them almost impossible to measure. However, it is possible to measure the adducts resulting from their binding to DNA or proteins (Hemoglobin and Albumin). The Cysteine34 (Cys34) locus of the Human Serum Albumin (HSA) represents a preferred reaction site for small electrophilic species. HSA has a long half-life in serum (30 days) and is present at high concentration; therefore, it is a good marker to measure exposure to toxic electrophiles. Up to now, current techniques have focussed on the targeted measure of pre-selected albumin-adducts in serum to detect exposure to certain chemicals. Although targeted assays can relate Cys34 adducts to specific exposures, they are not well suited for discovering unknown causes of human diseases arising from exposures to electrophilic species. In this project, we applied a new method based on high resolution mass spectrometry; this novel approach is based on an agnostic untargeted analysis of known and unknown adducts of albumin and electrophiles to determine oxidative stress. The objectives of EXACT were to (i) Apply agnostic adductomics to a nested case-control study of 250 prospective cases and controls of Lung Cancer (ii) Determine differential adducts profiles in cases and controls years before diagnosis (iii) Relate adduct profiles to exposure data and methylation measurements in order to elucidate biological pathways and exposure leading to lung cancer. Conclusions: For the first time we were able detect, in prospective blood samples, decreased levels of the N-acetylcysteine (NAC) and Cysteine-Glycine adducts in lung cancer cases. Altogether, our results highlight the implications of these adducts in the oxidative stress response contributing to lung cancer years before diagnosis.

Data: CORDIS, © European Union