Abstract
INTRODUCTION: Lung cancer is rare before age 45, and its inherited genetic basis remains poorly defined. METHODS: We performed whole-genome sequencing in 171 predominantly young-onset lung cancer patients and integrated these data with whole-exome sequencing from six major lung cancer consortia, yielding 9,065 patients. After quality control, analyses focused on 6,545 individuals of European ancestry, the largest ancestral group. We compared the prevalence of rare pathogenic and likely pathogenic (P/LP) germline variants between 186 young-onset (age <45 years) and 6,359 older patients at gene and gene-set levels using Fisher's exact test, stratified by histology, sex, and smoking status. Polygenic risk scores (PRS) derived from common variants were also evaluated. RESULTS: Young-onset patients carried a higher burden of rare germline P/LP variants in DNA damage response (DDR) genes (including BRIP1 , ERCC6 , MSH5), and in cilia-related genes, notably GPR161 . At the pathway level, DDR genes were significantly enriched (OR=1.66, p =0.007), with the strongest signal in the Fanconi Anemia pathway and among females (OR=1.96, p =0.01). Enrichment was also observed in inborn errors of immunity pathways, with strongest signals in antibody deficiency and the complement system genes. Young-onset patients additionally exhibited higher lung cancer PRS. CONCLUSION: Young-onset lung cancer exhibits a distinct germline genetic architecture, characterized by enrichment of rare P/LP variants in DDR, cilia-related, and immune pathways, and an elevated lung cancer PRS. These findings support a greater role for inherited susceptibility in early-onset disease and have implications for risk stratification, earlier screening, and precision prevention.