Krause A, Roma L, Lorber T, et al. - Adenosquamous carcinoma of the lung (ASC), a rare subtype of non-small cell lung cancer, is biphasic with lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) components with morphological features of classic LUAD and LUSC but acts more aggressively. Using whole exome sequencing (WES), researchers here explore the genomic landscape of macrodissected LUAD and LUSC components of three ASC. They identified truncal mutations that are characteristic for LUAD but uncommon in LUSC, including the pan-cancer tumor-suppressor gene TP53 as well as EGFR, BRAF, and MET. Mutational signatures of truncal mutations varied from those of the branch mutations in their descendants LUAD and LUSC. Aging and smoking were identified influencing the most common signatures. All three ASC were identified as sharing truncal chromosomal copy number aberrations including losses of 3p, 15q and 19p, and an amplified region in 5p. In addition, they identified loss of STK11 and SOX2 amplification in ASC, which has been identified in preclinical mouse models as a driver for transdifferentiation from LUAD to LUSC. In conclusion, this is the first research in which WES has been used to clarify the clonal evolution of ASC. Strong evidence was generated suggesting that the LUAD and LUSC components of ASC share a common origin and that the LUAD component seems to transform to LUSC.