Epigenetic inflammation signatures and lung cancer risk among never-smoking women: a nested case-control study

Chronic inflammation has been implicated in lung carcinogenesis. Prospective studies have linked higher circulating C-reactive protein (CRP), an acute-phase inflammation marker, to higher lung cancer risk in predominantly smoking populations but lower risk in never smokers. We evaluated DNA methylation-based inflammation risk scores (DNAm-IRSs), which may capture longer-term immune-inflammatory and exposure-related biology, with lung cancer risk among never smokers.

We evaluated six DNAm-IRSs, including four CRP-based scores (IRS_Ligthart, IRS_Wielscher, IRS_{Linear_Hillary}, IRS_{Elnet_Hillary}), in 683 risk-set-sampled case-control pairs nested in the Shanghai Women's Health Study (n=74,941). We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using conditional logistic regression. We examined DNAm-derived leukocyte composition and circulating immune-inflammatory proteins to characterize DNAm-IRS biology.

Circulating CRP correlated positively with IRS_Ligthart (r=0.19), IRS_Wielscher (r=0.13), and IRS_{Elnet_Hillary} (r=0.30), but inversely with IRS_{Linear_Hillary} (r=-0.02). Per standard deviation increase, IRS_Ligthart was associated with lower lung cancer risk (HR=0.85, 95% CI: 0.76-0.95), and IRS_Wielscher with lower risks of lung cancer (HR=0.87, 95% CI: 0.77-0.97) and adenocarcinoma (HR=0.83, 95% CI: 0.71-0.97). Associations persisted after adjustment for leukocyte composition and strengthened after adjustment for DNAm pack-years, an epigenetic smoking index that may capture combustion-related exposures beyond active smoking. Inverse associations were more evident among women with lower DNAm pack-years, although formal interaction tests were not statistically significant. Both scores were positively associated with acute-phase inflammation, IFN-γ/effector trafficking, and higher CD8+ T-cell proportions.

Among never smokers, selected CRP-related DNAm-IRSs were associated with lower lung cancer risk and were linked to immune features consistent with antitumor activity.