Krause Arthur, Roma Luca, Lorber Thomas, Habicht James, Lardinois Didier, De Filippo Maria Rosaria, Prince Spasenija Savic, Piscuoglio Salvatore, Ng CharlotteKY, Bubendorf Lukas
Institute of Molecular Genetics and Pathology, University Hospital Basel, University of Basel, Switzerland.
Thoracic Surgery, St. Clara Hospital, Basel, Switzerland.
Lung Cancer. 2020 Dec;150:132-138. doi: 10.1016/j.lungcan.2020.10.013. Epub 2020 Oct 29.
Adenosquamous carcinoma of the lung (ASC) is a rare subtype of non-small cell lung cancer, consisting of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) components. ASC shows morphological characteristics of classic LUAD and LUSC but behaves more aggressively. Although ASC can serve as a model of lung cancer heterogeneity and transdifferentiation, its genomic background remains poorly understood. In this study, we sought to explore the genomic landscape of macrodissected LUAD and LUSC components of three ASC using whole exome sequencing (WES). Identified truncal mutations included the pan-cancer tumor-suppressor gene TP53 but also EGFR, BRAF, and MET, which are characteristic for LUAD but uncommon in LUSC. No truncal mutation of classical LUSC driver mutations were found. Both components showed unique driver mutations that did not overlap between the three ASC. Mutational signatures of truncal mutations differed from those of the branch mutations in their descendants LUAD and LUSC. Most common signatures were related to aging (1, 5) and smoking (4). Truncal chromosomal copy number aberrations shared by all three ASC included losses of 3p, 15q and 19p, and an amplified region in 5p. Furthermore, we detected loss of STK11 and SOX2 amplification in ASC, which has previously been shown to drive transdifferentiation from LUAD to LUSC in preclinical mouse models. Conclusively, this is the first study using WES to elucidate the clonal evolution of ASC. It provides strong evidence that the LUAD and LUSC components of ASC share a common origin and that the LUAD component appears to transform to LUSC.
肺腺鳞癌（ASC）是一种罕见的非小细胞肺癌亚型，由肺腺癌（LUAD）和肺鳞状细胞癌（LUSC）成分组成。ASC具有经典LUAD和LUSC的形态学特征，但行为更具侵袭性。尽管ASC可作为肺癌异质性和转分化的模型，但其基因组背景仍知之甚少。在本研究中，我们试图通过全外显子测序（WES）探索3例ASC的大体解剖LUAD和LUSC成分的基因组格局。鉴定出的主干突变包括泛癌肿瘤抑制基因TP53，还有LUAD特征性但在LUSC中不常见的EGFR、BRAF和MET。未发现经典LUSC驱动突变的主干突变。两个成分均显示出独特的驱动突变，在3例ASC之间不重叠。主干突变的突变特征与其后代LUAD和LUSC中的分支突变不同。最常见的特征与衰老（1、5）和吸烟（4）有关。所有3例ASC共有的主干染色体拷贝数畸变包括3p、15q和19p缺失，以及5p的一个扩增区域。此外，我们在ASC中检测到STK11缺失和SOX2扩增，此前在临床前小鼠模型中已证明其可驱动从LUAD到LUSC的转分化。总之，这是第一项使用WES阐明ASC克隆进化的研究。它提供了强有力的证据，表明ASC的LUAD和LUSC成分有共同起源，且LUAD成分似乎会转变为LUSC。
