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.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This study was supported by The National Natural Science Foundation of China (No. 82002417), and the National Key Program of the Ministry of Science and Technology (No. 2020YFC2004505), and the Medical Scientific Research Foundation of Guangdong Provincial Health Commission (No. A2024060) and the Guangzhou National Laboratory (grant ZL-SRPG2200701 and YW-JCZD0104).