Epigenetic mechanisms of lung carcinogenesis involve differentially methylated CpG sites beyond those associated with smoking

Smoking-related epigenetic changes have been linked to lung cancer, but the contribution of epigenetic alterations unrelated to smoking remains unclear. We sought for a sparse set of CpG sites predicting lung cancer and explored the role of smoking in these associations. We analysed CpGs in relation to lung cancer in participants from two nested case–control studies, using (LASSO)-penalised regression. We accounted for the effects of smoking using known smoking-related CpGs, and through conditional-independence network. We identified 29 CpGs (8 smoking-related, 21 smoking-unrelated) associated with lung cancer. Models additionally adjusted for Comprehensive Smoking Index-(CSI) selected 1 smoking-related and 49 smoking-unrelated CpGs. Selected CpGs yielded excellent discriminatory performances, outperforming information provided by CSI only. Of the 8 selected smoking-related CpGs, two captured lung cancer-relevant effects of smoking that were missed by CSI. Further, the 50 CpGs identified in the CSI-adjusted model complementarily explained lung cancer risk. These markers may provide further insight into lung cancer carcinogenesis and help improving early identification of high-risk patients

DNA methylation changes measured in pre-diagnostic peripheral blood samples are associated with smoking and lung cancer risk

DNA methylation changes are associated with cigarette smoking. We used the Illumina Infinium HumanMethylation450 array to determine whether methylation in DNA from pre-diagnostic, peripheral blood samples is associated with lung cancer risk. We used a case-control study nested within the EPIC-Italy cohort and a study within the MCCS cohort as discovery sets (a total of 552 case-control pairs). We validated the top signals in 429 case-control pairs from another 3 studies. We identified six CpGs for which hypomethylation was associated with lung cancer risk: cg05575921 in the AHRR gene (p-valuepooled  = 4 × 10(-17) ), cg03636183 in the F2RL3 gene (p-valuepooled  = 2 × 10 (- 13) ), cg21566642 and cg05951221 in 2q37.1 (p-valuepooled  = 7 × 10(-16) and 1 × 10(-11) respectively), cg06126421 in 6p21.33 (p-valuepooled  = 2 × 10(-15) ) and cg23387569 in 12q14.1 (p-valuepooled  = 5 × 10(-7) ). For cg05951221 and cg23387569 the strength of association was virtually identical in never and current smokers. For all these CpGs except for cg23387569, the methylation levels were different across smoking categories in controls (p-valuesheterogeneity  ≤ 1.8 x10 (- 7) ), were lowest for current smokers and increased with time since quitting for former smokers. We observed a gain in discrimination between cases and controls measured by the area under the ROC curve of at least 8% (p-values ≥ 0.003) in former smokers by adding methylation at the 6 CpGs into risk prediction models including smoking status and number of pack-years. Our findings provide convincing evidence that smoking and possibly other factors lead to DNA methylation changes measurable in peripheral blood that may improve prediction of lung cancer risk

Natural vs anthropogenic components in sediments from the Po River delta coastal lagoons (NE Italy)

The Sacca di Goro and Sacca di Scardovari are two coastal lagoons of the Po River delta facing the northern Adriatic Sea. They are sensitive ecosystems both from the naturalistic and socio-economic point of view, since they are included in a natural park and are high productivity shellfish sites. Bottom sediments from the two lagoons have been analysed for their textural and geochemical (major and trace elements by XRF) composition in order to identify natural backgrounds and anthropogenic inputs. OC, N and δ13COC data have been also carried out by EA-IRMS to highlight the association of heavy metals with inorganic or organic sedimentary components. Results show that abundances of siderophile (Cr, Ni, Co) heavy metals in samples from the two lagoons are generally in the range of those recorded in alluvial sediments from the neighbours and are associated with the finest (clayey) fraction. Among chalcophile heavy metals, Pb and Zn display significant enrichments relative to the local geochemical backgrounds suggesting anthropogenic sources. They appear to be preferentially associated with the sedimentary organic matter that, according to the isotopic composition, is mainly formed by the incorporation of different proportions of macroalgae and macrophytes that have a significant bioaccumulation capacity. Taking into consideration that the extent of the algal biomass is sensitive to anthropogenic pressure and climatic changes, the trace element budget of sediments from these lagoons has to be monitored in the future, also to assess the impact of heavy metals on shellfish production