AHRR DNA Methylation Levels in Leukocytes Identify People at Risk for Cancer Mortality Overlooked by Questionnaire-Based Smoking Indices

BACKGROUND: Current evidence suggests an increased risk for cancer mortality in those with low aryl hydrocarbon receptor repressor (AHRR) DNA methylation (DNAm) levels. Therefore, AHRR DNAm could identify a more "fragile" group at risk for cancer mortality than questionnaire-based evaluations. Given this, the aim was to identify "fragile" groups at risk of cancer mortality by integrating questionnaire-based smoking indices and leukocyte AHRR DNAm levels in the Japanese population. METHODS: The target population was 795 participants without a clinical history who underwent a health checkup in 1990. They were followed for up to 30 years for mortality. The AHRR DNAm levels in leukocytes were measured by the pyrosequencing method. HRs for cancer mortality were calculated using a Cox proportional hazards model. RESULTS: Significantly higher HRs for all-cancer mortality were observed in low AHRR DNAm groups regardless of smoking intensity [pack-years <20: 3.69 (1.46-9.37); pack-years ≥20: 2.13 (1.11-4.09)]. Compared with current smokers, significantly lower HRs for all-cancer mortality were observed in the group with high AHRR DNAm regardless of years since quitting [YSQ ≤10: 0.13 (0.02-0.96); YSQ >10: 0.28 (0.08-0.98)]. Even for YSQ greater than 10, there was no significant mortality risk reduction in the low AHRR DNAm group. CONCLUSIONS: The population with low AHRR DNAm levels had a higher risk of cancer mortality even with low smoking exposure. Furthermore, no significant risk reduction was observed in former smokers with low AHRR DNAm levels. IMPACT: AHRR DNAm levels in leukocytes may help identify groups at risk for cancer mortality overlooked by questionnaire-based smoking indices.