Abstract
Recently, an increasing number of young never-smokers are diagnosed with lung cancer. The aim of this study is to investigate the genetic predisposition of lung cancer in these patients and discover candidate pathogenic variants for lung adenocarcinoma in young never-smokers. Peripheral blood was collected from 123 never-smoking east-Asian patients diagnosed with lung adenocarcinoma before the age of 40. Whole-exome sequencing (WES) was conducted on genomic DNA extracted from peripheral blood cells. As a result, 3,481 single nucleotide variants were identified. By bioinformatical tools and the published gene list associated with genetic predisposition of cancer, pathogenic variants were detected in ten germline genes: ATR, FANCD2, FANCE, GATA2, HFE, MSH2, PDGFRA, PMS2, SDHB, and WAS. Patients with pathogenic variants were more likely to occur in females (9/10, 90.0%) and have stage IV lung adenocarcinoma (4/10, 40%). Furthermore, germline mutations in 17 genes (ASB18, B3GALT5, CLEC4F, COL6A6, CYP4B1, C6orf132, EXO1, GATA4, HCK, KCP, NPHP4, PIGX, PPIL2, PPP1R3G, RRBP1, SALL4, and TTC28), which occurred in at least two patients, displayed potentially pathogenic effects. Gene ontology analysis further showed that these genes with germline mutations were mainly located in nucleoplasm and associated with DNA repair-related biological processes. The study provides spectrum of pathogenic variants and functional explanation for genetic predisposition of lung adenocarcinoma in young never-smokers, which sheds a light on prevention and early diagnosis of lung cancer.
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Data Availability
All the identified germline mutations in this study were listed in Supplementary Table 1, and clinical data were also included in Supplementary Table 2. The raw data of WES from 123 young nonsmoking patients with lung adenocarcinoma have been uploaded to the in the Genome Sequence Archive of the BIG Data Center at the Beijing Institute of Genomics, Chinese Academy of Science, China. They are accessible under HRA001459 (http://bigd.big.ac.cn/gsa-human/).
Code Availability
The codes are available from the corresponding authors upon reasonable request.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (81772466), Shanghai Rising-Star Program (21QC1400600), Ministry of Science and Technology of the People’s Republic of China (2017YFA0505500; 2016YFA0501800), and Science and Technology Commission of Shanghai Municipality (19XD1401300).
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Conceptualization: FF, XT, ZJ, YS, LS, and YZ. Methodology: FF, XT, ZJ, LS, YS, and YZ. Formal analysis and investigation: FF, XT, ZJ, ZG, YZ, YL. Writing—original draft: FF, XT, ZJ, HH, YS, and YZ. Writing—review and editing: FF, XT, ZJ, ZG, YZ, YL, HH, LS, YS, and YZ. Funding acquisition: YS and YZ. Resources: FF, XT, ZJ, ZG, YZ, YL, Hong Hu, LS, YS, and YZ. Supervision: LS, YS, and YZ.
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The Institutional Review Board of Fudan University Shanghai Cancer Center has approved this study (IRB#090977-1).
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Fu, F., Tao, X., Jiang, Z. et al. Identification of Germline Mutations in East-Asian Young Never-Smokers with Lung Adenocarcinoma by Whole-Exome Sequencing. Phenomics 3, 182–189 (2023). https://doi.org/10.1007/s43657-022-00062-1
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DOI: https://doi.org/10.1007/s43657-022-00062-1