Identification of the Unique Clinical and Genetic Features of Chinese Lung Cancer Patients With EGFR Germline Mutations in a Large-Scale Retrospective Study

Abstract

BackgroundEpidemiological surveys have suggested that lung cancer has inherited susceptibility and shows familial aggregation. However, the distribution and prevalence of epidermal growth factor receptor (EGFR) germline variants and their roles in lung cancer genetic predisposition in Chinese population remain to be elucidated.MethodsIn this study, EGFR germline and somatic variants were retrospectively reviewed from the next-generation sequencing results of 31,906 patients with lung cancer. Clinical information was also collected for patients with confirmed EGFR germline mutations.ResultsA total of 22 germline EGFR variants were identified in 64 patients with lung cancer, accounting for 0.2% of the total cases studied. Five patients were diagnosed as multiple primary carcinomas. Family history was documented in 31.3% (20/64) of patients, 55% of which were diagnosed as lung cancer. G863D was the most frequent EGFR germline mutation, followed by P848L, D1014N, and K757R. Somatic EGFR-sensitive mutations were identified in 51.6% of patients with germline EGFR mutations. The proportion of L858R mutation, exon 19 deletion, and rare sensitive mutation was 50%, 17.6%, and 32.4%, respectively. D1014N and T790M mutations were common in young patients. The family members of patients with P848L, R776H, V769M, and V774M mutations were more commonly diagnosed with cancers. A total of 19 patients were confirmed to have received EGFR tyrosine kinase inhibitors (TKIs), but the response to EGFR-TKIs differed among patients with different EGFR mutations.ConclusionChinese patients with lung cancer harbored unique and dispersive EGFR germline mutations and showed unique clinical and genetic characteristics, with varied response patterns to EGFR-TKI treatment.

Multiple primary lung cancer: Updates and perspectives

“…The same mutations were found in five paternal relatives of the patient, and three of them were also found to have multiple GGNs. Furthermore, a recent study enrolled 162 probands with MPLC showing an EGFR germline mutation rate as high as 9.8%, 112 which is far higher than the rate of 0.01% in the general population, 113 and approximately 0.2% in the entire set of lung cancer patients 114 . The rate of germline mutations in lung cancer varies between 0.2% and 7.0%, depending on the inclusion criteria and study settings, 115–123 and a recent study reports a rate reaching 15% in over 7000 unselected lung cancer, with 95% being clinically actionable 124 .…”

“…111 The same mutations were found in five paternal relatives of the patient, and three of them mutation rate as high as 9.8%, 112 which is far higher than the rate of 0.01% in the general population, 113 and approximately 0.2% in the entire set of lung cancer patients. 114 The rate of germline mutations in lung cancer varies between 0.2% and 7.0%, depending on the inclusion criteria and study settings, [115][116][117][118][119][120][121][122][123] and a recent study reports a rate reaching 15% in over 7000 unselected lung cancer, with 95% being clinically actionable. 124 Since individuals with MPLC appear to be more susceptible to germline mutations, along with the potential for high germline mutation rates in lung cancer, a potentially sizable MPLC population harboring targetable germline mutations should be anticipated, and targeting germline mutation may serve as a new therapeutic approach for MPLC in the future.…”

Non‐small cell lung cancer in China

“…Germline mutations of EGFR, V‐erb‐b2 avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2), checkpoint kinase 2 (CHEK2), and cyclin‐dependent kinase inhibitor 2A were detected in lung cancer patients [ 74 , 75 , 76 ]. In a large‐scale study of 31,926 Chinese lung cancer patients, 22 types of EGFR germline mutations were identified in 64 lung cancer individuals (0.2%), among which G863D was the most frequent type of mutation (14.1%, 9/64) [ 75 ]. In 12,833 Chinese lung cancer cases, 0.12% harbored EGFR germline mutation ( n = 14) [ 76 ].…”

Germline EGFR mutations in lung cancer (Review)

“…The morbidity of the P848L population is currently unclear. A large-scale retrospective study involving 31,906 Chinese patients with lung cancer found 22 germline EGFR variants in 64 patients with lung cancer, while germline EGFR P848L account for 10.9% (7/64) of the patients with EGFR germline mutation (29). A further study of 120 patients with colorectal or lung cancer reported that only one patient exhibited the P848L mutation (30).…”