Abstract 2287: A prospective investigation on DNA methylation-based inflammation risk scores and lung cancer among never smokers: findings from the Shanghai Women’s Health Study

Abstract Introduction: Inflammation plays a key role in cancer development, and C-reactive protein (CRP) is often studied as a biomarker, though its association with lung cancer remains inconsistent. We previously reported an inverse association between plasma CRP levels and lung cancer development in never-smoking women in the Shanghai Women’s Health Study (SWHS). However, as CRP levels fluctuate with active inflammation, a single measurement may not accurately capture the inflammatory responses relevant to cancer development. DNA methylation-based inflammation risk scores (DNAm-IRS) provide a more stable, integrative measure of long-term inflammation. To date, only one prospective study, primarily in smokers, has examined DNAm-IRS and lung cancer risk, showing an inverse association after adjusting for DNAm-derived smoking patterns. In this study, we expand our previous research by more than doubling the number of lung cancer cases and controls and incorporating CRP-derived DNAm-IRS to investigate associations with lung cancer in never smokers. Methods: This nested case-control study, conducted within the prospective SWHS, included 683 never-smoking women with incident lung cancer and 683 never-smoking controls, matched on date of birth (±2 years) and sample collection time (±3 months). Four DNAm-IRS were calculated as the weighted sum of CRP-related CpG sites (52 for IRSLigthart, 1, 334 for IRSElnet, 1, 333 for IRSWielscher, and 32, 196 for IRSHillary) using established algorithms. Conditional logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI), adjusting for age and body mass index. Results: Among controls with available plasma CRP levels (n = 214), the Spearman correlation coefficients between biochemical CRP and DNAm-IRS derived from CRP were as follows: 0.20 (p=3.4×10-3) for IRSLigthart, 0.31 (p=4.6×10-6) for IRSElnet, 0.13 (p=6.7×10-2) for IRSWielscher, and -0.02 (p=7.4×10-1) for IRSHillary. Higher DNAm-IRS scores were associated with a reduced risk of lung cancer among never-smoking women. Specifically, each standard deviation (SD) increase in IRSWielscher was associated with a 13% lower risk of overall lung cancer (95% CI: 0.77-0.97; p=0.017) and a 17% lower risk of lung adenocarcinoma (95% CI: 0.71-0.97; p=0.018), the most common histologic subtype. Additionally, IRSLigthart was associated with a 15% lower risk of overall lung cancer (95% CI: 0.78-0.97; p=0.003). Conclusion: Our findings, along with prior research, suggest that certain aspects of CRP are paradoxically associated with a reduced risk of lung cancer in never-smokers or when analysis accounts for DNAm-derived smoking patterns. Further studies are warranted to replicate these findings and investigate the underlying biological mechanisms. Citation Format: Mohammad L. Rahman, Aishani Gargapati, Wei Zheng, Jason Y.Y Wong, Jianxin Shi, Charles E. Breeze, Batel Blechter, Wei Hu, Qiuyin Cai, Gong Yang, Jirong Long, Yu-Tang Gao, Nathaniel Rothman, Xiao-Ou Shu, Qing Lan. A prospective investigation on DNA methylation-based inflammation risk scores and lung cancer among never smokers: findings from the Shanghai Women’s Health Study [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 2287.