We measured human serum albumin (HSA) untargeted adductomics profiles in 250 plasma samples from the prospective lung cancer cases (median follow up 7 years) and healthy controls from the Italian component of the European Prospective Investigation into Cancer and Nutrition (EPIC-Italy) cohort. To determine the implication of tobacco smoke, we used detailed information on smoking status, smoking intensity, time since cessation and the comprehensive smoking index. The levels of exposure to air pollution at participants’ homes were estimated via land-use regression models. Individual levels for 2 gases: NO2 and NOx, fine particles with a diameter of 2.5 µg/m3 (PM2.5) and 10 µg/m3 (PM10) were estimated. We evaluated the association between each given adduct and (i) exposure to tobacco smoke, (ii) exposure to air pollution and (iii) prospective lung cancer status using linear mixed models. Our models accounted for several important characteristics of the participants such as gender, age, centre of recruitment and BMI as well as technical variables. In order to further understand the role of exposure to tobacco smoke in lung carcinogenesis with adductomics, we explored the association linking adducts levels to 2670 assayed methylation CpG sites that were determined as epigenetics markers smoking in previous work.
We identified 42 (including 14 novel) HSA adducts. Our analysis of lung cancer outcome identified 6 differentially abundant adducts in prospective cases compared to controls (p<0.05). Among these, the adduct of N-acetylcysteine, a powerful anti-oxidant, showed the stronger association, with lower levels in future cases than controls. The lower abundance of the NAC adduct in cases may reflect the lower bioavailability of NAC in serum suggestive of dysregulation of redox control. As we disposed of a very limited number of non-smoking Lung Cancer cases, only very week associations of adducts levels and exposure to air pollution were observed. The level of the NAC adduct was associated to the methylation levels of 11 smoking-related CpG sites. Our findings are consistent with a perturbation in redox pathways and consequently a potential imbalance in ROS levels and elimination in future lung cancer cases.
Altogether this approach provides interesting new insights in lung carcinogenesis and highlights the ability of HSA adductomics to explore the biological processes by which oxidative stress and redox balance dysregulation may contribute, years before clinical manifestations, to carcinogenesis and to investigate the role of smoking in these processes
The developments and findings of EXACT have been published in 1 peer-reviewed journal article, 1 edited book, 2 international conferences and 2 invited talks. Additional publications are currently planned (2 submitted, 1 in preparation). The results of EXACT have been presented to the REA in the context of the EXPOSOMICS project. EXACT has contributed to public outreach activities, the project has been presented at the Imperial College Festival 2017 and 2018, the MRC Festival 2017 and Imperial Fringe 2017 reaching out to the general public and school students.
