Abstract 4958: Prediagnostic peripheral blood DNA methylation and lung cancer survival
Authors: Doherty Jennifer A. , Zhang Xuan , Koestler Devin C. , Barnett Matt J. , Thornquist Mark D. , Goodman Gary E. , Marsit Carmen J. 
Published: July 2017

Abstract
Epigenetic regulation plays a critical role in cell and tissue development and differentiation, is a known mechanism of carcinogenesis, and is altered by various exposures including cigarette smoking and age. Peripheral blood methylation represents a combination of these factors as well as blood cell type distributions that reflect underlying immunophenotypes. Hematopoiesis is programmed through epigenetic changes, and blood cell type-specific methylation markers can be leveraged to “fingerprint” cell type distributions. We examined associations between pre-diagnostic methylation markers in peripheral blood with overall lung cancer survival in very heavy smokers from the Beta Carotene and Retinol Efficacy Trial (CARET). CARET was a randomized, double-blinded, placebo-controlled chemoprevention trial of daily β-carotene and retinyl palmitate in smokers with ≥20 pack-years, and smokers who were occupationally exposed to asbestos. Methylation was successfully measured using the Illumina 850K EPIC BeadArray on average 5 years prior to diagnosis for 331 lung cancer cases, of whom 253 died during follow up (median survival 329 days). Cox proportional hazards regression models were used to examine the relationship between CpG-specific methylation and survival. Models were adjusted for age at blood draw, sex, race, enrollment year, placebo/active intervention, asbestos exposure, current/former smoking and time since quit, pack years, average number of cigarettes per day and histologic type, and were fit separately depending on the time between blood draw and lung cancer diagnosis: 0-3 years (n = 107), 3-5 years (n = 77), and 5+ years (n = 147). After adjusting for multiple comparisons by computing the false discovery rate (FDR) q-value, there were 1,028, 296, and 4 CpGs that were statistically significantly associated with survival (q ≤0.010) for samples collected 0-3 years, 3-5 years, and 5+ years before diagnosis, respectively. After controlling for blood cell type distributions, much larger numbers of CpGs were statistically significantly associated with survival: 10,481, 456, and 257, respectively. The top canonical pathways of CpGs identified in samples drawn 0-3 years prior to diagnosis included PTEN signaling (p = 1.1E-5) and PI3K signaling in B lymphoctyes (p = 3.7E-5). We observed that the number of methylated CpGs in peripheral blood that are associated with subsequent survival increases dramatically when measured closer to lung cancer diagnosis. As well, we observed that the number of methylated markers is increased by controlling for immunophenotype. Our study provides evidence that peripheral blood methylation markers measured many years prior to diagnosis may be associated with poor lung cancer survival, and that increasing changes in methylation over time may also be associated. This points to the critical role of the immune system, even prior to diagnosis, in influencing cancer outcomes.
Citation Format: Jennifer A. Doherty, Xuan Zhang, Devin C. Koestler, Matt J. Barnett, Mark D. Thornquist, Gary E. Goodman, Carmen J. Marsit. Prediagnostic peripheral blood DNA methylation and lung cancer survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4958. doi:10.1158/1538-7445.AM2017-4958