Therapeutic targets for lung cancer: genome-wide Mendelian randomization and colocalization analyses

Yi Luan; Desheng Xian; Changwen Zhao; Xin Qing; Hanlin He; Kaixuan Zheng; Wenjun Song; Taijiao Jiang; Wenjian Wang; Chaohui Duan

doi:10.3389/fphar.2024.1441233

Therapeutic targets for lung cancer: genome-wide Mendelian randomization and colocalization analyses

Front Pharmacol. 2024 Oct 28:15:1441233. doi: 10.3389/fphar.2024.1441233. eCollection 2024.

Authors

Yi Luan^{1

2}, Desheng Xian³, Changwen Zhao³, Xin Qing⁴, Hanlin He^{1

5}, Kaixuan Zheng^{1

6}, Wenjun Song¹, Taijiao Jiang^{1

7}, Wenjian Wang^{8

9

10}, Chaohui Duan^{1

9}

Affiliations

¹ Laboratory Testing and Diagnosis Technology Department of Guangzhou National Laboratory, Clinical Laboratory of Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, China.
² School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
³ State Key Laboratory of Chemical Resource Engineering and Beijing Laboratory of Biomedical Materials, Key Laboratory of Biomedical Materials of Natural Macromolecules, Ministry of Education, University of Chemical Technology, Beijing, China.
⁴ Westchina Hospital, Sichuan University, Chengdu, China.
⁵ Guangzhou Medical University, Guangzhou, Guangdong, China.
⁶ School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China.
⁷ State Key Laboratory of Respiratory Disease, The Key Laboratory of Advanced Interdisciplinary Studies Center, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
⁸ Department of Thoracic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
⁹ Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
¹⁰ Department of Thoracic Surgery, Shenshan Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Shanwei, Guangdong, China.

Abstract

Background: Lung cancer, categorized into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), remains a significant global health challenge. The development of drug resistance and the heterogeneity of the disease necessitate the identification of novel therapeutic targets to improve patient outcomes.

Methods: We conducted a genome-wide Mendelian randomization (MR) and colocalization analysis using a comprehensive dataset of 4,302 druggable genes and cis-expressed quantitative trait loci (cis-eQTLs) from 31,884 blood samples. The study integrated genomic analysis with eQTL data to identify key genes associated with lung cancer risk.

Results: The analysis revealed five actionable therapeutic targets for NSCLC, including LTB4R, LTBP4, MPI, PSMA4, and TCN2. Notably, PSMA4 demonstrated a strong association with both NSCLC and SCLC risks, with odds ratios of 3.168 and 3.183, respectively. Colocalization analysis indicated a shared genetic etiology between these gene expressions and lung cancer risk.

Conclusion: Our findings contribute to precision medicine by identifying druggable targets that may be exploited for subtype-specific lung cancer therapies.

Keywords: GWAS; Mendelian randomization; colocalization analyses; drug target; lung cancer.