Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts

Abstract

DNA hypomethylation in certain genes is associated with tobacco exposure but it is unknown whether these methylation changes translate into increased lung cancer risk. In an epigenome-wide study of DNA from pre-diagnostic blood samples from 132 case–control pairs in the NOWAC cohort, we observe that the most significant associations with lung cancer risk are for cg05575921 in AHRR (OR for 1 s.d.=0.37, 95% CI: 0.31–0.54, P-value=3.3 × 10−11) and cg03636183 in F2RL3 (OR for 1 s.d.=0.40, 95% CI: 0.31–0.56, P-value=3.9 × 10−10), previously shown to be strongly hypomethylated in smokers. These associations remain significant after adjustment for smoking and are confirmed in additional 664 case–control pairs tightly matched for smoking from the MCCS, NSHDS and EPIC HD cohorts. The replication and mediation analyses suggest that residual confounding is unlikely to explain the observed associations and that hypomethylation of these CpG sites may mediate the effect of tobacco on lung cancer risk.

Smoking-associated DNA methylation markers predict lung cancer incidence

“…These findings are corroborated and expanded by our current findings, which were derived from a larger number of LC cases with DNA methylation being assessed by a different method that is regarded as a gold-standard technique for methylation analyses at specific sites [29]. During preparation of the current manuscript, an EWAS conducted in pre-diagnostic blood samples of LC cases and controls was published, where AHRR _cg05575921, 6p21.33 _cg06126421, and F2RL3 _cg03636183 methylation were again ranked as the top CpGs inversely associated with LC risk [30]. The researchers further validated these associations in 664 case-control pairs matched for smoking from another 3 large cohorts.…”

“…Performance of these markers appears superior to the performance of the smoking-associated DNA methylation markers assessed in our study. However, these studies evaluated the markers’ performance in retrospective studies with cases already diagnosed as LC and biospecimen collected at/after diagnosis, while the 3 smoking-associated markers were evaluated in prospectively collected samples either in the current study or in the EWAS by Fasanelli et al [30]. The average time interval between sample collection and diagnosis of LC was 5.3 years in the current study and 3.8–9.6 years in the 4 case sets of Fasanelli’s study [30].…”

Hypermethylation of adjacent CpG sites is negatively correlated with the expression of lineage oncogeneASCL1in pulmonary neuroendocrine tumors

“…Our findings are supported by previous reports that smoking is associated with hypomethylation of one or more CpG site(s) or with specific genes in lung cancer. 34 Finally, we believe that the methylation levels of CpG_6.7.8 can be used as a diagnostic marker for distinguishing LCNEC from SCLC (sensitivity = 80%, specificity = 70%, cut-off value = 0.115) in some difficult cases.…”

Is Cellular Heterogeneity Merely a Confounder to be Removed from Epigenome-Wide Association Studies?

“…Although epigenetic programming was originally envisioned to pertain to very early life factors (i.e., fetal programming, see for example [14]), it could be generalized to account for environmental influences throughout the lifecourse. Some of the best evidence for the later life effect of the environment on DNA methylation is from Fasanelli and colleagues, who showed (by EWAS) that smoking reversibly caused hypomethylation of the AHRR and FR2L3 genes in adults and that approximately 37% of the total effect of smoking on lung cancer risk is mediated by methylation at these loci [15]. Importantly, these findings have recently been independently replicated [16].…”