Lung cancer in never smokers (LCINS) is a common cause of cancer mortality but its genomic landscape is poorly characterized. Here high-coverage whole-genome sequencing of 232 LCINS showed 3 subtypes defined by copy number aberrations. The dominant subtype (piano), which is rare in lung cancer in smokers, features somatic UBA1 mutations, germline AR variants and stem cell-like properties, including low mutational burden, high intratumor heterogeneity, long telomeres, frequent KRAS mutations and slow growth, as suggested by the occurrence of cancer drivers’ progenitor cells many years before tumor diagnosis. The other subtypes are characterized by specific amplifications and EGFR mutations (mezzo-forte) and whole-genome doubling (forte). No strong tobacco smoking signatures were detected, even in cases with exposure to secondhand tobacco smoke. Genes within the receptor tyrosine kinase–Ras pathway had distinct impacts on survival; five genomic alterations independently doubled mortality. These findings create avenues for personalized treatment in LCINS.

从不吸烟者肺癌 (LCINS) 是癌症死亡的常见原因，但其基因组图谱尚不清楚。此处，232 个 LCINS 的高覆盖率全基因组测序显示了由拷贝数畸变定义的 3 种亚型。显性亚型（piano）在吸烟者肺癌中罕见，具有体细胞UBA1突变、种系AR变异和干细胞样特性，包括低突变负荷、高肿瘤内异质性、长端粒、频繁的KRAS突变和生长缓慢，正如肿瘤诊断前许多年癌症驱动祖细胞的出现所表明的那样。其他亚型的特点是特异性扩增和EGFR突变 (mezzo-forte) 和全基因组加倍 (forte)。即使在接触二手烟草烟雾的情况下，也没有检测到强烈的吸烟特征。受体酪氨酸激酶-Ras 通路内的基因对生存有明显的影响；五项基因组改变独立地使死亡率加倍。这些发现为 LCINS 的个性化治疗创造了途径。