Abstract
BACKGROUND AND AIM: Smoking is a well-known carcinogen consistently associated with differential DNA methylation in diverse populations. Dysregulations of DNA methylation have been associated with lung cancer. Smoking and lung cancer are common among many indigenous communities of the United States, leading to health disparities. This study investigated the potential mediating role of DNA methylation changes in the association of smoking with incident smoking-related cancers. METHODS: DNA methylation was measured in blood collected at baseline (1989-1991) using the EPIC 850K platform in 2351 American Indian participants of the Strong Heart Study. Cancer incidence was available through 2017 (97 cases for lung cancer, 222 cases for a combined smoking-related cancer endpoint including lung, esophageal, stomach, colorectal, liver, pancreatic and kidney cancers). Iterative Sure Independence Screening paired with adaptive elastic-net was used to select differentially methylated CpGs associated with cancer. Mediation analysis using Aalen additive hazard models was then applied to the selected CpGs. RESULTS:At total of 71 CpGs were associated with lung cancer and smoking-related cancer. For lung cancer, we found significant mediated effects for seven CpGs for current versus former or never smoking, and for eight CpGs for cumulative smoking. For smoking-related cancers, we found significant mediated associations for eight CpGs for current versus former or never smoking, and for one CpG for cumulative smoking. CpGs annotated to the AHRR and the PRSS23 genes (well-known smoking-related genes in DNA methylation studies), showed up to 70 % and up to 48 % of relative mediated effects, respectively, without accounting for multiple mediation. CONCLUSIONS:Our study provides strong evidence that a large extent of the association of smoking with smoking-related cancers, especially in lung cancer, can be explained by differential DNA methylation changes in well-known smoking related genes. Replication is ongoing in the Framingham Heart Study and the Rotterdam Study. KEYWORDS: Smoking, DNA methylation, cancer, American Indians
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