Abstract 2263: DNA methylation-estimated C-reactive protein levels and lung cancer risk and mortality in individuals with a heavy smoking history

Abstract Inflammation, a hallmark of cancer and chronic disease, is an established risk factor for lung cancer and is also associated with worse survival in lung cancer cases. C-reactive protein (CRP) is one circulating biomarker of inflammation that has been shown to be associated with DNA methylation (DNAm) in epigenome-wide association studies (EWAS). Several epigenetic CRP scores have been proposed using results from these studies, offering the unique opportunity to approximate CRP in studies without directly measured CRP. A validated DNAm CRP score was recently published by Hillary et al., which explains 18% of CRP variation beyond age, sex, and CRP-based genotype. This score, mCRP, includes 1,468 CpGs obtained from elastic net regression on EWAS results for measured CRP in a training set of nearly 18k individuals. Using an additive linear combination of the published CpGs and EWAS regression weights, we estimated pre-diagnosis mCRP in individuals with a heavy smoking history from the β-Carotene and Retinol Efficacy Trial (CARET) and assessed associations with both lung cancer risk and mortality for all cases and by histotype. Analytic samples included: 316 lung cancer case-control pairs through 2005, matched on age (±5 years), sex, race and ethnicity, enrollment year (±2 years), smoking status (ever/never), asbestos exposure, and follow-up time, (mean 57 pack years, range 11-185) for risk; and 372 lung cancer cases diagnosed through 2013 (mean 59 pack years, range 20-162) for mortality. DNAm data was assayed on the Illumina EPIC array in blood collected on average 4.3 years before diagnosis in cases for risk and 4.9 years for mortality. Conditional logistic regression models adjusted for age and pack years revealed no strong evidence of increased lung cancer risk with increasing mCRP. Cox proportional hazards models adjusted for age, sex, smoking status (current/former), pack years, and time from blood draw to diagnosis with stage as a stratification variable (early I/II, advanced III/IV, unknown) showed a greater hazard of death per standard deviation increase in mCRP among all lung cancer cases (Hazard Ratio (HR) 1.13, CI: 1.02-1.25), adenocarcinoma (HR 1.21, CI: 1.02-1.43), and small cell carcinoma (SCLC; HR 1.33, CI: 1.06-1.68). No associations were observed for squamous cell carcinoma, and results were similar for lung cancer-specific mortality among each case group. While these results do not provide support that pre-diagnosis mCRP is associated with lung cancer risk in individuals with a heavy smoking history, we observed that greater pre-diagnosis mCRP may be an indicator of mortality in members of this population. This work highlights the possible importance of pre-diagnosis inflammation via mCRP and mortality in heavy smokers who later develop lung cancer, particularly adenocarcinoma and SCLC. Citation Format: Laurie Grieshober, Stefan Graw, Matt J. Barnett, Gary E. Goodman, Chu Chen, Devin C. Koestler, Carmen J. Marsit, Jennifer A. Doherty. DNA methylation-estimated C-reactive protein levels and lung cancer risk and mortality in individuals with a heavy smoking history [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2263.