LAUSR

Introduction: Inherited genetic determinants of lung cancer risk remain relatively elusive. Germline mutations in EGFR and erb‐b2 receptor tyrosine kinase 2 (ERBB2) have been previously reported in lung cancers that may be associated with genetic susceptibility to lung cancer. Methods: We retrospectively analyzed a cohort of 12,833 Chinese lung cancer patients tested by targeted next‐generation sequencing. Patients with EGFR and ERBB2 germline mutations were identified, and their clinical information and family history were summarized. Growth factor independency of EGFR germline mutations was further analyzed in vitro. Results: Eight different heterozygous EGFR germline mutations from 14 adenocarcinoma patients (0.12%) were identified within or adjacent to the kinase domain, including K757R (n = 5), R831H (n = 2), D1014N (n = 2), G724S, V786M, T790M, L792F, and L844V. Only one patient harbored the ERBB2‐V1128I germline mutation. Five of 15 patients had family history of cancer. Notably, the patient with EGFR‐T790M germline mutation had multiple maternal family members diagnosed with lung cancers, strongly supporting its role in inherited lung cancer. Concurrent known somatic driver mutations were not detected in 5 patients at diagnosis, 1 of whom harbored the EGFR‐L844V germline mutation and showed superior response to afatinib. Consistently, EGFR‐K757R and L844V mutations were able to be interleukin 3 – independent in vitro and were sensitive to EGFR tyrosine kinase inhibitors. Conclusions: EGFR/ERBB2 germline mutations were found to be rare in Chinese lung cancer patients with more diversity other than the previously reported EGFR‐T790M, with EGFR‐K757R being the most common EGFR germline mutation. Patients with EGFR germline mutations without other known driver mutations might benefit from tyrosine kinase inhibitor treatment.