Individual and joint contributions of genetic and methylation risk scores for enhancing lung cancer risk stratification: data from a population-based cohort in Germany

Background Risk stratification for lung cancer (LC) screening is so far mostly based on smoking history. This study aimed to assess if and to what extent such risk stratification could be enhanced by additional consideration of genetic risk scores (GRSs) and epigenetic risk scores defined by DNA methylation. Methods We conducted a nested case-control study of 143 incident LC cases and 1460 LC-free controls within a prospective cohort of 9949 participants aged 50-75 years with 14-year follow-up. Lifetime smoking history was obtained in detail at recruitment. We built a GRS based on 31 previously identified LC-associated single-nucleotide polymorphisms (SNPs) and a DNA methylation score (MRS) based on methylation of 151 previously identified smoking-associated cytosine-phosphate-guanine (CpG) loci. We evaluated associations of GRS and MRS with LC incidence by logistic regression models, controlling for age, sex, smoking status, and pack-years. We compared the predictive performance of models based on pack-years alone with models additionally including GRS and/or MRS using the area under the receiver operating characteristic curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Results GRS and MRS showed moderate and strong associations with LC risk even after comprehensive adjustment for smoking history (adjusted odds ratio [95% CI] comparing highest with lowest quartile 1.93 [1.05-3.71] and 5.64 [2.13-17.03], respectively). Similar associations were also observed within the risk groups of ever and heavy smokers. Addition of GRS and MRS furthermore strongly enhanced LC prediction beyond prediction by pack-years (increase of optimism-corrected AUC among heavy smokers from 0.605 to 0.654, NRI 26.7%,p= 0.0106, IDI 3.35%,p= 0.0036), the increase being mostly attributable to the inclusion of MRS. Conclusions Consideration of MRS, by itself or in combination with GRS, may strongly enhance LC risk stratification.