Abstract 3424: Assessing a DNA methylation-based telomere length estimator in individuals with a heavy smoking history

Abstract Telomere length (TL) and DNA methylation are associated with age and smoking exposure, as well as aging-related outcomes including lung cancer and mortality. A DNA methylation-based TL score (DNAmTL) was developed to estimate TL using DNA methylation array data, both in blood. DNAmTL effectively estimates telomere-related aging using 140 CpGs that are moderately enriched in sub-telomeric regions and not included in existing epigenetic clocks. We examined DNAmTL in individuals with a heavy smoking history (mean 56 pack years, range 11-185) in a nested lung cancer case-control study of 350 cases and 350 controls from the β-Carotene and Retinol Efficacy Trial identified through 2005. Twenty-two controls became cases with additional follow-up through 2013, so 328 controls and 372 cases were considered for these analyses. Leukocyte TL was measured using quantitative polymerase chain reaction (T/S ratio, log2-transformed), and DNA methylation was assayed on the Illumina EPIC array, in blood samples obtained on average 4.9 years prior to diagnosis in cases. We observed weak positive Pearson correlations between DNAmTL and TL in cases (r=0.19, p=0.0003) and controls (r=0.14, p=0.009) that persisted after age-adjustment: r=0.16, p=0.002 and r=0.14, p=0.014, respectively. Age-adjusted DNAmTL, but not TL, was longer for female compared to male cases (T=3.6, p=0.0004) and controls (T=2.2, p=0.03), and for those in the placebo compared to the intervention arm in cases (T=2.1, p=0.03) and controls (T=2.3, p=0.02). Linear regression models of TL and DNAmTL adjusted for age, sex, and race and ethnicity were not statistically significant for smoking variables at blood draw (pack years, current vs former smoking status, cigarettes smoked per day during smoking history, years smoked, years since quit), nor asbestos exposure in either cases or controls. Longer age-adjusted DNAmTL was associated with a lower hazard ratio (HR) for time to lung cancer death (0.60, 95% Confidence Interval (CI): 0.37-0.97) among cases (n=313 lung cancer-specific mortality events) in Cox proportional hazards models adjusted for age, sex, race and ethnicity, and time from blood draw to diagnosis with stage as a stratification variable (early I/II, advanced III/IV, unknown). Analogous age-adjusted TL model showed a similar direction but did not reach statistical significance (HR 0.86, CI: 0.71-1.05). Further adjustment of these models by DNA methylation-estimated leukocyte proportions of granulocytes, monocytes, natural killer, CD8+T, and CD4+T (excluding B cells) yielded similar results for age-adjusted DNAmTL (HR 0.54, CI: 0.31-0.92) and age-adjusted TL (HR 0.87, CI: 0.71-1.05). Our results illustrate that while DNAmTL may not be closely associated with smoking exposure among heavily exposed individuals, shorter DNAmTL may be more strongly associated with lung cancer mortality than TL in individuals with a heavy smoking history. Citation Format: Laurie Grieshober, Stefan Graw, Matt J. Barnett, Gary E. Goodman, Chu Chen, Devin C. Koestler, Carmen J. Marsit, Jennifer A. Doherty. Assessing a DNA methylation-based telomere length estimator in individuals with a heavy smoking history [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3424.