Data from <i>AHRR</i> DNA Methylation Levels in Leukocytes Identify People at Risk for Cancer Mortality Overlooked by Questionnaire-Based Smoking Indices

<div>AbstractBackground:<p>Current evidence suggests an increased risk for cancer mortality in those with low aryl hydrocarbon receptor repressor (<i>AHRR</i>) DNA methylation (DNAm) levels. Therefore, <i>AHRR</i> 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 <i>AHRR</i> DNAm levels in the Japanese population.</p>Methods:<p>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 <i>AHRR</i> DNAm levels in leukocytes were measured by the pyrosequencing method. HRs for cancer mortality were calculated using a Cox proportional hazards model.</p>Results:<p>Significantly higher HRs for all-cancer mortality were observed in low <i>AHRR</i> 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 <i>AHRR</i> 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 <i>AHRR</i> DNAm group.</p>Conclusions:<p>The population with low <i>AHRR</i> 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 <i>AHRR</i> DNAm levels.</p>Impact:<p><i>AHRR</i> DNAm levels in leukocytes may help identify groups at risk for cancer mortality overlooked by questionnaire-based smoking indices.</p></div>