Identification of pathogenic germline variants in a large Chinese lung cancer cohort by clinical sequencing

Genetic factors play significant roles in the tumorigenicity of lung cancer; however, there is lack of systematic and large-scale characterization of pathogenic germline variants for lung cancer. In this study, germline variants in 146 preselected cancer-susceptibility genes were detected in 17 904 Chinese lung cancer patients by clinical next-generation sequencing. Among 17 904 patients, 1738 patients (9.7%) carried 1840 pathogenic/likely pathogenic (P/LP) variants from 87 cancer-susceptibility genes. SBDS (SBDS ribosome maturation factor) (1.37%), TSHR (thyroid stimulating hormone receptor) (1.20%), BLM (BLM RecQ like helicase) (0.62%), BRCA2 (BRCA2 DNA repair associated) (0.62%), and ATM (ATM serine/threonine kinase) (0.45%) were the top five genes with the highest overall prevalence. The top mutated pathways were all involved in DNA damage repair (DDR). Case-control analysis showed SBDS c.184A>T(p.K62*), TSHR c.1574T>C(p.F525S), BRIP1 (BRCA1 interacting helicase 1) c.1018C>T(p.L340F), and MUTYH (mutY DNA glycosylase) c.55C>T(p.R19*) were significantly associated with increased lung cancer risk (q value < 0.05). P/LP variants in certain genes were associated with early onset of lung cancer. Our study indicates that Chinese lung cancer patients have a higher prevalence of P/LP variants than previously reported. P/LP variants are distributed in multiple pathways and dominated by DNA damage repair-associated pathways. The association between identified P/LP variants and lung cancer risk requires further studies for verification.