Genetic insights into pulmonary nodules and lung cancer: similarities and differences revealed by GWAS studies.
Authors
Affiliations (8)
Affiliations (8)
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, Jiangsu Province 211166, China.
- State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, Jiangsu Province 211166, China.
- Department of cancer prevention, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, No. 1 East Banshan Road, Gongshu District, Hangzhou, Zhejiang Province 310022, China.
- Department of Chronic Non-Communicable Disease Control, The Affiliated Wuxi Center for Disease Control and Prevention of Nanjing Medical University, Wuxi Center for Disease Control and Prevention, Wuxi Medical Center, Nanjing Medical University, No. 499 Jincheng Road, Liangxi District, Wuxi, Jiangsu Province 214023, China.
- Department of Cancer Prevention, Taizhou Cancer Hospital, No. 50 Zhenxin Road, Xinhe Town, Wenling, Taizhou, Zhejiang Province 317502, China.
- Department of Radiology, Taizhou Cancer Hospital, No. 50 Zhenxin Road, Xinhe Town, Wenling, Taizhou, Zhejiang Province 317502, China.
- Department of Health Promotion Center, the First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Gulou District, Nanjing, Jiangsu Province 210029, China.
- Department of Radiology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, No. 1 East Banshan Road, Gongshu District, Hangzhou, Zhejiang Province 310022, China.
Abstract
The widespread implementation of low-dose computed tomography (LDCT) has markedly increased the detection of pulmonary nodules, yet their genetic determinants remain poorly understood. We conducted a genome-wide association study (GWAS) of 36 175 LDCT-screened individuals from Zhejiang and Jiangsu provinces in China, assessing fourteen pulmonary nodule phenotypes defined using a convolutional neural network-based computer-aided detection (CNN-CAD) system. We identified eleven independent single-nucleotide polymorphisms (SNPs) at nine loci associated with nodule phenotypes. Functional annotation prioritized six candidate genes with either missense variants or strong colocalization evidence, including TP63 at 3q28, PLA2G4F at 15q15.1, HLA-DRB6 and CYP21A2 at 6p21.32, TNFSF11 at 13q14.11, and TNFRSF11B at 8q24.12. These genes were enriched in pathways related to cell adhesion, chemotaxis, cytokine activity, and lymphocyte activation. Several of the identified variants-associated with non-solid components, nodule size, and the number of positive nodules-were also significantly associated with increased malignancy probability of pulmonary nodules. Genetic correlation analysis revealed a substantial shared genetic basis between purely ground-glass nodules (pGGNs) and lung adenocarcinoma (LUAD) (rg = 0.79; 95% CI, 0.16-1.42; P = 0.014), and Mendelian randomization (MR) further supported a potential causal relationship, with an odds ratio (OR) of 51.1 (95% CI: 1.13-2035.31). These findings offer novel insights into the genetic architecture of pulmonary nodules and highlight a substantial genetic overlap between pGGNs and LUAD, which may inform risk prediction and precision prevention in lung cancer screening.