Background: Impaired lung function (LF) is strongly associated with increased lung cancer risk. However, since airflow obstruction is a diagnostic criterion for obstructive lung disease, and a consequence of tobacco smoking, isolating the causal relationship between LF and lung cancer has remained a challenge.
Methods: We investigated 3 standardized (mean=0, standard deviation=1) LF metrics: forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC. To evaluate the causal relevance of LF in lung cancer etiology we conducted: i) survival analyses in the UK Biobank cohort (UKB); and ii) Mendelian Randomization (MR) analyses using genetic instrumental variables (IVs) developed in UKB and tested using individual-level data from the OncoArray, a genome-wide array with in-depth coverage for common cancers. Results: 702 incident lung cancers were diagnosed in 484,194 UKB participants during follow-up. Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI), adjusted for age, sex, smoking status, socioeconomic status, and assessment center. Adjustment for other smoking metrics yielded similar results. Lung cancer risk increased per 1 unit decrease in FEV1 (HR=1.80, 95% CI: 1.64-1.98, p=3.3×10-34), FVC (HR=1.45, 1.30-1.60, p=2.3×10-12), and FEV1/FVC (HR=1.39, 1.33-1.46, p=1.3×10-38). This pattern was observed for adenocarcinoma (n=300): FEV1 (HR=1.77, p=6.0×10-12), FVC (HR=1.48, p=1.4×10-5), FEV1/FVC (HR=1.34, p=8.3×10-11); and squamous cell carcinoma (n=166): FEV1 (HR=1.97, p=9.9×10-10), FVC (HR=1.60, p=1.0×10-4), FEV1/FVC (HR=1.38, p=5.9×10-8). Next, a genome-wide association study of 67,708 UKB participants and 12.6 million variants was carried out to develop genetic IVs for LF.
Results were filtered to retain independent variants (R2<0.2) associated with each LF phenotype (p<5×10-8). The following IVs were developed: FEV1 (n=28 variants, 0.72% of variation explained), FVC (n=44, 1.08%), and FEV1/FVC (n=45, 1.85%). Odds ratios (OR) for each IV and lung cancer were estimated for 18,686 cases 15,190 controls (>80% European ancestry) from 23 studies. Effect estimates were combined using maximum-likelihood MR models to estimate causal ORs. MR results indicate that genetic scores associated with improved airflow are unrelated to lung cancer risk: FEV1 (OR=1.00, 95% CI: 0.96-1.03, p=0.86), FVC (OR=1.00, 0.97-1.03, p=0.93) and FEV1/FVC (OR=1.00, 0.91-1.10, p=0.95). The null association observed for the genetic determinants of FEV1, FVC and FEV1/FVC was not modified by tumor histology or smoking status.
Conclusions: LF is a robust predictor of lung cancer risk, however, our findings do not support the existence of causal pathways that are independent of obstructive lung disease or smoking. This apparent lack of a causal relationship should be interpreted with caution since pleiotropic effects of LF loci cannot be ruled out.