Identification of Germline Mutations in East-Asian Young Never-Smokers with Lung Adenocarcinoma by Whole-Exome Sequencing

Fangqiu Fu; Xiaoting Tao; Zhonglin Jiang; Zhendong Gao; Yue Zhao; Yuan Li; Hong Hu; Libing Shen; Yihua Sun; Yang Zhang

doi:10.1007/s43657-022-00062-1

Identification of Germline Mutations in East-Asian Young Never-Smokers with Lung Adenocarcinoma by Whole-Exome Sequencing

Phenomics. 2022 Jun 11;3(2):182-189. doi: 10.1007/s43657-022-00062-1. eCollection 2023 Apr.

Authors

Fangqiu Fu^#^{1

2

3}, Xiaoting Tao^#^{1

2

3}, Zhonglin Jiang^#⁴, Zhendong Gao^{1

2

3}, Yue Zhao^{1

2

3}, Yuan Li^{2

3

5}, Hong Hu^{1

2

3}, Libing Shen⁶, Yihua Sun^{1

2

3}, Yang Zhang^{1

2

3}

Affiliations

¹ Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032 China.
² Institute of Thoracic Oncology, Fudan University, Shanghai, 200032 China.
³ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032 China.
⁴ Key Laboratory of Systems Biology, Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031 China.
⁵ Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032 China.
⁶ International Human Phenome Institutes (Shanghai), Shanghai, 200433 China.

^# Contributed equally.

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.

Supplementary information: The online version contains supplementary material available at 10.1007/s43657-022-00062-1.

Keywords: DNA repair; Germline mutation; Lung adenocarcinoma; Never-smoker; Young age.