Deciphering the clonal relationship between glandular and squamous components in adenosquamous carcinoma of the lung using whole exome sequencing

Abstract

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.

Comprehensive molecular characterization of lung tumors implicates AKT and MYC signaling in adenocarcinoma to squamous cell transdifferentiation

“…We refer to the genetically related samples hereafter as T-LUAD and T-LUSC with the T referring to histologic transdifferentiation, with no presumption of directionality. These results further support the existence of lineage plasticity in adenosquamous samples, consistent with previous reports [ 7 , 36 ].

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“…Our epigenomic and transcriptomic data indicate that T-LUSC exhibits a molecular profile close to that of LUAD, but distinct from that of de novo LUSC. These results support a role for lineage plasticity in their development, rather than colocalization of independent tumors, as previously suggested [ 7 , 36 ]. The directionality of transformation in adenosquamous cases cannot be assumed, and it is possible that both histologies arise in parallel establishing a cooperative relationship, as has been previously reported for other tumor types in which distinct intratumoral subpopulations cooperate to promote therapeutic resistance or metastasis [ 61 ].…”

“…More recently, histologic transdifferentiation of LUAD to squamous carcinoma of the lung (LUSC) has also been observed in association with acquired resistance to highly active targeted therapies [ 4 – 6 ]. Interestingly, even if targeted agents may promote transdifferentiation, the existence of untreated adenosquamous tumors containing areas of LUAD and LUSC showing shared driver alterations in both histological components [ 7 , 8 ] suggests that this lineage plasticity phenomenon may occur in the absence of the selective pressure exerted by treatment. Mixed histology non-small cell lung cancer has a remarkably poor prognosis across stage, significantly worse than either LUAD or LUSC [ 9 ].…”

“…Adenosquamous carcinomas containing discrete areas of LUAD and LUSC histology amenable for physical isolation for independent molecular analyses may provide insight into lineage plasticity along this axis. The occurrence of common driver mutations in both histologic components in such cases [ 7 , 8 ] suggests a recent divergence in phenotypic commitment to adenomatous vs. squamous lineages. We hypothesized that defining common genetic and epigenetic differences between LUAD and LUSC components in the constrained environment of these mixed histology tumors could define candidate determinants of LUAD to LUSC transdifferentiation, which could be subsequently validated in manipulable models.…”

Genomic evolutionary trajectory of metastatic squamous cell carcinoma of the lung

“…As described by Murugaesu et al, a maximum parsimony tree was built for each case using binary presence/absence matrices based on the repertoire of non-synonymous and synonymous somatic mutations in the biopsies of the tumors (25)(26)(27).…”