Epigenome-wide scan identifies differentially methylated regions for lung cancer using pre-diagnostic peripheral blood

Abstract

Background: To reduce lung cancer burden in the US, a better understanding of biological mechanisms in early disease development could provide new opportunities for risk stratification. Methods: In a nested case-control study, we measured blood leukocyte DNA methylation levels in pre-diagnostic samples collected from 430 men and women in the 1989 CLUE II cohort. Median time from blood drawn to diagnosis was 14 years for all participants. We compared DNA methylation levels by case/control status to identify novel genomic regions, both single CpG sites and differentially methylated regions (DMRs), while controlling for known DNA methylation changes associated with smoking using a previously described pack-years based smoking methylation score. Stratification analyses were conducted by time from blood draw to diagnosis, histology, and smoking status. Results: We identified sixteen single CpG sites and forty DMRs significantly associated with lung cancer risk (q < 0.05). The identified genomic regions were associated with genes including H19, HOXA4, RUNX3, BRICD5, PLXNB2, and RP13. For the single CpG sites, the strongest association was noted for cg09736286 in the DIABLO gene (OR [for 1 SD] = 2.99, 95% CI: 1.95-4.59, P-value = 4.81 x 10-7). For the DMRs, we found that CpG sites in the HOXA4 region were hypermethylated in cases compared to controls. Conclusion: The single CpG sites and DMRs that we identified represented significant measurable differences in lung cancer risk, providing new insights into the biological processes of early lung cancer development and potential biomarkers for lung cancer risk stratification.

Phenome-wide analysis identifies parent-of-origin effects on the human methylome associated with changes in the rate of aging

“…Importantly, we detected cases where the same single POE-CpG was simultaneously associated with both environmental exposure (such as maternal smoking exposure or lifestyle), adult aging and/or with health-related phenotypes (such as intelligence). Our observation of the associations between cg14391737, an intronic POE-CpG located of gene PRSS23 , with smoking status and forced expiratory flow (Figure 5), was in line with previous MWAS papers that identified cg14391737 as a smoking- and lung cancer-associated CpG (67, 68). Here, we uncovered its additional associations with education, socioeconomic status and DNAmTL acceleration.…”

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

“…The fact that we highlighted novel, smoking-unrelated CpG sites upon accounting for the effect of CSI, tends to be in line with former investigations, which also capture weaker effect-size and more heterogeneous signals when compared to the generally conserved smoking-related epigenetic signature (i.e. AHRR-cg05575921, F2RL3-cg03636183) [15]. Among these 49 smoking-unrelated markers, 33 were found hypomethylated and 17 hypermethylated in lung cancer cases, and our discussion will be restricted to those presenting stronger effects and a high selection proportion (|β|> 0.5, selection proportion > 0.9, N = 14).…”

“…Several studies have investigated the role and potentially mediating molecular pathways affected by smokingrelated epigenetic changes in relation to lung carcinogenesis [11][12][13][14][15], but so far, the potential contribution of smokingindependent epigenetic modifications to lung cancer development remains understudied.…”