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

Sep 22, 2026

Growing scientific evidence suggested that hepatocyte growth factor (HGF) may play a crucial role in lung cancer development, potentially influenced by the epidermal growth factor (EGF)/EGF receptor. A Mendelian randomization study assessed whether gene-determined elevated plasma HGF causally increases lung cancer risk and its subtypes, and whether EGF mediates these effects. Thirteen HGF instrumental variants from European GWAS data and lung cancer GWAS datasets were analyzed using IVW MR with sensitivity checks and mediated analysis, plus reverse-MR and pleiotropy testing.

LanguageEnglish

CategoryResearch & Report

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Pages7

Reading Time18 min

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Introduction

Mendelian randomization study design

Mediation analysis with EGF

Sensitivity and reverse-causality assessments

® Observational Study Association of genetically determined plasma hepatocyte growth factor with lung cancer and its subtypes Mendelian randomization and mediation analysis Feiqi Xu, MDa , Qingyun Xu, MDb , Jiamian Yu, MDb , Yanna Le, MPHb , Hong Fu, MDb , Xiaoying Ruan, MDb , Yanpeng Shi, MDb , Lin Zhu, MDb , Jianrong Chai, MDb , Yu Zhou, MDb , Lan Ding, MDa , Yanyan Shi, MDa ,* | Abstract
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. | | --- | | Abbreviations: CI = confidence intervals, EGF = epidermal growth factor, EGFR-TKI = epidermal growth factor receptortyrosine kinase inhibitors, GWAS = genome-wide association study, HGF = hepatocyte growth factor, IVW = inversevariance weighted, LUAD = lung adenocarcinoma, LUSC = lung squamous cell cancer, MR = Mendelian randomization, MR-PRESSO = Mendelian randomization-pleiotropy residual sum and outlier, OR = odds ratios, RAPS = robust adjusted profile score, SCLC = small cell lung cancer, SD = standard deviation, TRICL-ILCCO = Transdisciplinary Research in Cancer of the Lung and the International Lung Cancer Consortium. | | Keywords: epidermal growth factor, hepatocyte growth factor, lung adenocarcinoma, lung cancer, Mendelian randomization | FX and QX contributed to this article equally. This study was supported by the Zhejiang Province Health and Wellness Plan (Young Innovative Talent Program, Grant: 2022RC006). The authors have no conflicts of interest to disclose. The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Supplemental Digital Content is available for this article. a Cancer Center, Department of

FAQs

What was the main goal of the study?

To test whether genetically determined elevated plasma hepatocyte growth factor (HGF) causally affects the risk of lung cancer and its subtypes, and to evaluate whether EGF mediates these associations.

How were associations between plasma HGF and lung cancer assessed?

Using Mendelian randomization with inverse-variance weighted (IVW) analysis, followed by multiple sensitivity analyses with different MR methods, plus reverse-MR to check for reverse causality.

What role did EGF play according to the mediated analysis?

The study found that EGF mediated the causal associations of HGF with lung cancer and lung adenocarcinoma, with mediation effects of 28.56% and 21.2%, respectively.

Sep 22, 2026

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