Genomic profiles of pathogenic and moderate-penetrance germline variants associated with risk of early-onset lung adenocarcinoma

Area of Science:

• Oncology
• Genetics
• Cancer Research

Background:

• Lung adenocarcinoma (LADC) disproportionately affects never-smoking Asian women, suggesting non-smoking factors are key.
• Genetic predisposition may significantly influence early-onset LADC development.

Purpose of the Study:

• Investigate the prevalence of germline pathogenic variants (GPVs) in hereditary cancer and DNA repair genes.
• Identify genetic factors contributing to early-onset LADC in Asian populations.

Main Methods:

• Whole-exome and whole-genome sequencing of 350 early-onset and 1,441 later-onset LADC cases.
• Case-control study of 10,672 LADC cases and 7,898 controls to identify moderate-risk genetic factors.
• Somatic mutation analysis in 1,280 LADC patients, including those with GPVs.

Main Results:

• TP53 and BRCA2 GPVs were significantly more frequent in early-onset LADC (2.9% and 1.7%) compared to later-onset LADC (0.14% and 0.21%).
• BRCA1 GPVs correlated with TP53 somatic mutations, and BRCA2 GPVs indicated homologous recombination deficiency.
• A novel germline ALKBH2 variant (p.Glu35Alafs*54) was associated with early-onset LADC risk and specific somatic mutation patterns.

Conclusions:

• TP53 and BRCA2 GPVs are significant risk factors for early-onset LADC in Asian individuals.
• A newly identified ALKBH2 germline variant is also implicated in the development of early-onset LADC.