Abstract
BackgroundRisk 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.MethodsWe 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).ResultsGRS 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.ConclusionsConsideration of MRS, by itself or in combination with GRS, may strongly enhance LC risk stratification.
Highlights
Risk stratification for lung cancer (LC) screening is so far mostly based on smoking history
Randomized trials have demonstrated that the potential of reducing LC mortality by screening the high-risk group of heavy smokers with low-dose computed tomography (LDCT) [6, 7]
Dozens of singlenucleotide polymorphisms (SNPs) associated with LC risk have been identified through genome-wide association studies (GWAS) [9]
Summary
Risk stratification for lung cancer (LC) screening is so far mostly based on smoking history. Survival and prognosis may be much better when LC is detected at an early stage through the use of screening [6]. Risk stratification for LC screening is so far mostly based on smoking history [7]. Genetic risk scores (GRS) based on SNPs identified from GWAS studies were found to enhance performance of risk prediction models for several common illnesses, such as cardiovascular disease [10], diabetes [11, 12], breast cancer [13, 14], colorectal cancer [15], and prostate cancer [16, 17]. Few studies have evaluated the contributions of GRS to risk stratification of LC
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
