NEW genomic data highlight a strong association between specific germline mutations and early-onset lung adenocarcinoma (LADC) in Asian populations, particularly among never-smoking women.
Up to 54% of lung adenocarcinoma cases in Asian populations occur in women who have never smoked, pointing to a limited role for environmental factors in disease development and raising the likelihood of underlying genetic susceptibility. To investigate this, researchers conducted whole-exome and whole-genome sequencing on 350 early-onset LADC patients (diagnosed before age 40) and 1,441 later-onset cases. They examined germline pathogenic variants (GPVs) in 454 genes linked to hereditary cancer and DNA repair. A case-control analysis involving over 10,000 LADC patients and 7,898 healthy individuals identified moderate-risk genetic factors, while somatic mutation profiles were also analysed in 1,280 tumour samples.
The prevalence of TP53 and BRCA2 GPVs was significantly higher in early-onset versus later-onset cases. Among early-onset patients, 2.9% carried TP53 variants and 1.7% carried BRCA2 variants, compared with just 0.14% and 0.21% in later-onset patients, respectively. BRCA1 GPV carriers often had concurrent TP53 somatic mutations, while BRCA2 GPV carriers exhibited tumour-specific homologous recombination deficiency through loss of the wild-type allele. Additionally, a novel germline variant in ALKBH2 (p.Glu35Alafs*54) was associated with increased risk of early-onset LADC. Patients with this variant also displayed SBS4-type somatic mutational signatures, which were significantly correlated with smoking intensity as measured by the Brinkman index, despite being predominantly never-smokers.
The findings emphasise the critical role of germline mutations, particularly in TP53, BRCA2, and ALKBH2, in the development of early-onset LADC in Asian populations. Genetic screening in young patients may enable earlier diagnosis and more personalised treatment strategies.
Reference
Cho H et al. Genomic profiles of pathogenic and moderate-penetrance germline variants associated with risk of early-onset lung adenocarcinoma. J Thorac Oncol. 2025; DOI:10.1016/j.jtho.2025.06.005.
