LAUSR

frequencies of mutation and copy number alterations, mutation signatures, intratumor heterogeneity, pathway alterations, and histology as well as overall survival were performed. We found that deleterious mutation burden was significantly greater in invasive ADC. Intratumor heterogeneity occurs as early as in AIS. More copy number loss was observed in AIS/MIA. Twenty-one significantly mutated genes were shared among three groups. Mutation signature profiling had no significant difference among three groups, although APOBEC signature was associated with ADC subgroup and poor survival. Mutations of KRAS, TP53, and NF1 were found at an increasing frequency from AIS/ MIA to ADC. A cancer progression model revealed selective early and late drivers. Subclonal KRAS mutations and a gene signature consisting of PIK3CG, ATM, EPPK1, EP300, or KMT2C mutations were associated with poor survival. Our results demonstrate several sequences of genetic driver events, gene clonality, and mutated gene signatures associated with outcome in early lung ADC with potential future implications in the management of early ADC.