Genomic Profiles of Pathogenic and Moderate-Penetrance Germline Variants Associated With Risk of Early-Onset Lung Adenocarcinoma

INTRODUCTION: Up to 54% of all lung adenocarcinoma (LADC) cases in Asian populations occur in never-smoking women, suggesting that the impact of smoking and other environmental factors on the risk of early-onset LADC is minimal. Genetic factors may play a crucial role in disease development. METHODS: The prevalence of germline pathogenic variants (GPVs) of 454 hereditary cancer and DNA repair genes was evaluated by whole-exome and whole-genome sequencing of 348 early-onset LADC (aged ≤ 40 y) and 1425 later-onset LADC (aged ≥ 41 y) cases. A case-control study comprising 10,302 LADC cases and 7898 healthy controls was performed to identify moderate-risk genetic factors for the disease. Analysis of somatic mutations in 1278 patients with LADC, including 31 patients with GPVs, was also performed. RESULTS: The frequency of GPVs of TP53 and BRCA2 was significantly higher in those with early-onset LADC than in those with later-onset LADC. The detection rates for TP53 and BRCA2 GPVs were 2.9% and 1.7%, respectively, in patients with early-onset LADC, and 0.14% and 0.21%, respectively, in patients with later-onset LADC. Patients with BRCA1 GPVs exhibited a high incidence of concurrent TP53 somatic mutations. Patients with BRCA2 GPVs exhibited deficient homologous recombination in tumors by means of loss of the wild-type allele. A germline ALKBH2 variant, p.Glu35Alafs∗54, was associated with the risk of early-onset LADC, and patients with a deleterious variant exhibited a correlation between SBS4-related somatic mutations and the Brinkman index. CONCLUSION: TP53 and BRCA2 GPVs and the ALKBH2 novel variant are associated with early-onset LADC in Asians.