Genomic and evolutionary classification of lung cancer in never smokers

Lung cancer in never smokers (LCINS) is a common cause of cancer mortality, but is poorly characterized. Here we show, through high coverage whole genome sequencing of 232 tumors (Sherlock-Lung study), that LCINS can be separated into three subtypes, defined by somatic copy number aberrations. While the dominant subtype (‘piano’), rarely found in lung cancer from smokers, is characterized by quiet copy number profiles, the other subtypes are associated with specific arm-level amplifications and EGFR mutations (‘mezzo-forte’), and whole genome doubling (‘forte’). Piano tumors feature somatic UBA1 mutations, germline AR variants, and stem cell-like properties, including low mutational burden, infrequent TP53 alterations, high intra-tumor heterogeneity, long telomeres, and slow growth as suggested by the occurrence of cancer driver genes decades prior to tumor diagnosis. To assess the stem cell-like features in piano tumors, we performed bulk RNA-seq from our Sherlock-Lung study including 35 adenocarcinomas (16 Piano, 8 Mezzo-forte, 11 Forte) and 32 tumor-paired normal lung tissue. We compared expression of gene sets included in differnt stem-cell signatures and and the finding suggests that less differentiated and a lineage infidelity in paino subtype, which could be the signs of stemness.