Genomic profiling implicates candidate genes and mutagenic pathways driving lung cancer recurrence

ABSTRACT Lung cancer remains the leading cause of cancer-related deaths worldwide, with tumor recurrence a major contributor to its high mortality. The genetic and molecular mechanisms of recurrence remain poorly understood. Using whole-exome sequencing of 155 primary non-small cell lung cancers, we studied the mutational landscape and driver alterations associated with recurrence. Primary tumors that developed recurrence had higher mutational burden, including hypermutated tumors explained by mutations in DNA polymerase or mismatch repair pathways. Mutational signatures of reactive oxygen species were associated with recurrence. Combined mutations in TP53 and CDKN2A were enriched in non-recurrent tumors, while ATRNL1 mutations were enriched in recurrent tumors. Pathway analyses implicated DNA repair and cilium organisation processes with tumor recurrence and highlighted 50 additional candidate genes including BRCA2 . Recurrence-associated genes showed essentiality in lung cancer cell lines and included known therapeutic markers, indicating their functional and translational relevance. This analysis provides insights into the molecular basis of lung cancer recurrence and informs experiments to develop diagnostic and therapeutic strategies.