AHRR (cg5575921) methylation safely improves specificity of lung cancer screening eligibility criteria.

Background: Screening reduces lung cancer mortality, but specificities of eligibility criteria are low. We tested if leukocyte AHRR(cg05575921) methylation improves specificity of lung cancer screening eligibility criteria.
Methods: 9,206 and 5,370 individuals of the 1991-94 and 2001-03 examinations of the Copenhagen City Heart Study, Denmark were followed for lung cancer within 5 years after examination and mortality. Screening eligibility criteria (DANTE, DLCST, ITALUNG, LUSI, NELSON, NLST and PLCOM2012) were evaluated, and AHRR(cg05575921) methylation extent at different methylation cut points was added. The model with the lowest number of eligible individuals per 5-year lung cancer was validated within the 2001-03 examination.
Results: Eligibility criteria identified risk-groups ranging from 3,182 (DANTE) to 1,641 (ITALUNG) individuals. The positive predictive value was highest for PLCOM2012 (3.2 %), while DANTE showed the highest negative predictive value (99.7%). Adding AHRR(cg05575921) methylation led to higher specificities for all criteria. Number of eligible individuals per 5-year lung cancer varied from 38 (NELSON) to 27 (NLST) with AHRR(cg05575921) methylation <55%. This last model led to a 21.9% lower screening burden and increased (p<0.05) specificity of 84.0%. Findings were reproduced among the 5,334 individuals of the 2001-03 examination.
Conclusions: Adding AHRR(cg05575921) methylation on top of current eligibility criteria for lung cancer screening improves specificity by excluding those individuals with the lowest risk.
Impact: The results points towards a potential clinical use of AHRR(cg05575921) methylation, which is a cost-effective measurement compared to lung CT scanning, to provide additional predictive risk information to identify eligible smokers for lung cancer screening.