Profiling Oncogenic Germline Mutations in Unselected Chinese Lung Cancer Patients.

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

doi:10.3389/fonc.2021.647598

Abstract

IntroductionEmerging 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.MethodsSequencing 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.ResultsSeven 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.ConclusionWe present the first study to systemically characterize the germline mutation in oncogenic driver genes in a large cohort of unselected patients with lung cancers.

Highlights

Emerging evidence has suggested that inherited factors are involved in lung cancer development
A previous study in 12,833 Chinese lung cancer patients focusing on epidermal growth factor receptor (EGFR) and ERBB2 has revealed a prevalence of 0.11 and 0.01% for germline mutations in the former and the latter, respectively [15]
The spectrum of mutations differs between two studies: of the eight EGFR germline mutations identified from Lu et al, only p.T790M and p.V786M were detected in our cohort

Summary

Introduction

Emerging evidence has suggested that inherited factors are involved in lung cancer development. Lung cancer is the most prevalent cancer worldwide and the leading cause of cancer-related mortality [1], which is partially attributable to its diagnosis at advanced stages. Environmental factors, such as tobacco exposure and air pollution, are generally considered as major etiological factors for lung tumorigenesis [2]. Mounting evidence has suggested that inherited factors are involved in lung cancer development. The vast majority of these studies focused on previously identified cancer predisposition genes (mostly tumor suppressor genes) and demonstrated that lung cancer patients, especially those with adenocarcinoma, harbor enriched germline mutations in DNA repair genes [8,9,10,11]

Methods

Results

Conclusion