Although carcinogens in tobacco smo

Although carcinogens in tobacco smoke are largely responsible for the mutagenesis in lung cancers (19), the wide range of mutation burden within both smokers and never-smokers implicates additional pathways contributing to the accumulation of somatic mutations. We found deleterious mutations in a number of genes that are important in DNA repair and replication. For example, in three responders with the highest mutation burden, we identified deleterious mutations in POLD1, POLE, and MSH2 (Fig. 3). Of particular interest, a POLD1 E374K mutation was identified in a never-smoker with DCB whose tumor harbored the greatest nonsynonymous mutation burden (n = 507) of all never-smokers in our series. POLD1 Glu374 lies in the exonuclease proofreading domain of Pol δ (20), and mutation of this residue may contribute to low-fidelity replication of the lagging DNA strand. Consistent with this hypothesis, this tumor exome had a relatively low proportion of C-to-A transversions (20%) and predominance of C-to-T transitions (51%), similar to other POLD1 mutant, hypermutated tumors (21) and distinct from smoking-related lung cancers. Another responder, with the greatest mutation burden in our series, had a C284Y mutation in POLD1, which is also located in the exonuclease proofreading domain. We observed nonsense mutations in PRKDC, the catalytic subunit of DNA-dependent protein kinase (DNA-PK), and RAD17. Both genes are required for proper DNA repair and maintenance of genomic integrity