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/blood pairs, 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. In contrast, driver mutations in mezzo-forte and forte tumors are generally late clonal events acquired close to tumor diagnosis, thus potentially facilitating target identification with a single biopsy. The mutational signature associated with direct exposure to tobacco smoking (SBS4) was not observed in our study, even in cases with reported exposure to second-hand tobacco smoke. No significant differences of mutational spectra were found between passive and non-passive smokers. While genes within the RTK-RAS pathway have distinct impacts on survival, mutations in TP53, CHEK2, EGFR, or loss of 15q or 22q independently doubled mortality. These genomic alterations in forte and mezzo-forte subtypes, and stem cell-like features in piano tumors create avenues for personalized therapeutic strategies in LCINS.

Citation Format: Tongwu Zhang, Ludmil B. Alexandrov, Wei Zhao, Jian Sang, Jianxin Shi, Bin Zhu, Dmitry A. Gordenin, Montserrat Garcia-Closas, Qing Lan, Nathaniel Rothman, Stephen J. Chanock, David C. Wedge, Maria Teresa Landi. Genomic and evolutionary classification of lung cancer in never smokers from the Sherlock-Lung study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 865.