Association of genetically determined plasma hepatocyte growth factor with lung cancer and its subtypes: Mendelian randomization and mediation analysis

Growing scientific evidence suggested that hepatocyte growth factor (HGF) might play a crucial role in the development of lung cancer, which might be influenced by the epidermal growth factor (EGF)/EGF receptor. However, the specific causality behind the association has not been clarified due to potential bias. Thus, a Mendelian randomization (MR) study was conducted to investigate the effects of gene-determined elevated plasma HGF on the risk of lung cancer and its subtypes, as well as the mediating effects of EGF. Thirteen instrumental variants for plasma HGF were derived from a genome-wide association study (GWAS) with 21,758 European participants, presented in SCALLOP consortium. Datasets of lung cancer and its subtypes (lung adenocarcinoma [LUAD], lung squamous cell cancer [LUSC], and small cell lung cancer [SCLC]) were based on a GWAS conducted by the Transdisciplinary Research in Cancer of the Lung and the International Lung Cancer Consortium (TRICL-ILCCO) with 29,266 lung cancer cases and 56,450 controls of European descent. We employed the inverse-variance weighted (IVW) MR analysis followed by a series of sensitive analyses to evaluate the associations between genetically determined plasma HGF and the risk of lung cancer and its subtypes. The primary IVW analysis showed that genetically determined HGF was associated with an increased risk of total lung cancer (odds ratio: 1.11, 95% confidence interval [CI]: 1.05–1.17, P  = 2.27E−04) and LUAD (odds ratio: 1.18, 95% CI: 1.09–1.27, P  = 1.47E−05) but not with LUSC and SCLC, by the sensitivity analyses with different MR methods further confirming these findings. Additionally, mediated analysis demonstrated that EGF mediated the causal associations of HGF with lung cancer and LUAD, with mediating effects of 28.56% and 21.2% on them. Besides, reverse-MR studies further confirmed no reverse causality between lung cancer and plasma HGF. The intercept of MR-Egger regression showed no directional pleiotropy for all associations ( P  > .05). Upregulated genetically determined plasma HGF levels were associated with an increasing risk of lung cancer, especially for LUAD. Mediated regulation of EGF on these associations indicated a potential pathogenesis pathway in lung cancer, which provides important implications for the prevention and management of lung cancer.