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

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. 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. 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. TP53 and BRCA2 GPVs and the ALKBH2 novel variant are associated with early-onset LADC in Asians.