Profiling Oncogenic Germline Mutations in Unselected Chinese Lung Cancer Patients

Jie Yang; Hefei Li; Ben Li; Wei Li; Qiang Guo; Ling Hu; Zizheng Song; Bin Zhou

doi:10.3389/fonc.2021.647598

Profiling Oncogenic Germline Mutations in Unselected Chinese Lung Cancer Patients

Front Oncol. 2021 Apr 7:11:647598. doi: 10.3389/fonc.2021.647598. eCollection 2021.

Authors

Jie Yang¹, Hefei Li², Ben Li², Wei Li², Qiang Guo², Ling Hu³, Zizheng Song³, Bin Zhou²

Affiliations

¹ Radiotherapy Department, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
² Department of Thoracic Surgery, Affiliated Hospital of Hebei University, Baoding, China.
³ Department of Medical Oncology, Affiliated Hospital of Hebei University, Baoding, China.

Abstract

Introduction: Emerging evidence has suggested that inherited factors are also involved in lung cancer development. However, most studies focused on well-elucidated cancer predisposition genes, the majority of which are tumor suppressor genes. The profile of germline mutations in oncogenic driver genes remains unrevealed, which might also provide potential clinical implications for lung cancer management.

Methods: Sequencing data from 36,813 unselected lung cancer patients who underwent somatic mutation profiling were retrospectively reviewed. All recruited patients had matched white blood cell samples sequenced in parallel using a capture-based panel including eight key lung cancer driver genes (epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), MET proto-oncogene, receptor tyrosine kinase (MET), Kirsten rat sarcoma viral oncogene homolog (KRAS), Erb-B2 receptor tyrosine kinase 2(ERBB2), ROS proto-oncogene 1, receptor tyrosine kinase (ROS1), ret proto-oncogene (RET), and B-Raf proto-oncogene, serine/threonine kinase (BRAF)). Likely pathogenic/pathogenic (LP/P) variants were called according to the classification criteria of the American College of Medical Genetics and Genomics. Variants of uncertain significance (VUS) located in the kinase domains of driver genes and occurring recurrently (n ≥3) were also included for further analyses.

Results: Seven different LP/P variants in EGFR, MET, or RET were identified in 0.03% of lung cancer patients (n = 14) and 25 different VUS in the kinase domains of seven driver genes (except KRAS) were found with a prevalence of 0.3% (n = 117).Collectively, germline mutations were most frequently seen in ROS1 (n = 31, 0.084%), followed by MET (n = 23, 0.062%), EGFR (n = 22, 0.06%), ALK (n = 22, 0.06%) and RET (n = 17, 0.046%). LP/P variants and VUS fell the most commonly in EGFR (n = 10, 72%) and ROS1 (n = 31, 26%), respectively. Of the 10 patients with EGFR LP/P germline mutation, 70% also acquired somatic EGFR driver mutation exon21 p.L858R or exon19 deletion at baseline; while the three patients with pathogenic germline RET mutation displayed distinct baseline somatic profiles of rare EGFR mutation or KRAS exon2 p.G12C. We discovered 11 germline mutations that also occurred somatically, including four LP/P variants and seven VUS.

Conclusion: We present the first study to systemically characterize the germline mutation in oncogenic driver genes in a large cohort of unselected patients with lung cancers.

Keywords: germline mutation; likely pathogenic/pathogenic variant; lung cancers; oncogenic gene; variants of uncertain significance.