Abstract 2515: Comprehensive analysis of the histologically distinct components of an adenosquamous carcinoma of the lung

Abstract

Abstract Background: Adenosquamous carcinoma (ASC) is a rare subtype of non-small-cell lung cancer, consisting of an adenocarcinoma (AC) and a squamous cell carcinoma (SCC) component. Little is known about the molecular makeup of the two components in ASC. In this study, we applied a comprehensive analysis including whole exome sequencing (WES) and RNA sequencing to understand the evolutionary relationship between the AC and SCC components of an ASC of the lung. Methods:FFPE tumor tissue of three ASC patients was used in this study. Samples were stained with FastRed to visualize the nuclei. AC and SCC components were scratched separately from histological slides for DNA and RNA extraction. WES analysis was performed to assess the mutational profile and copy number alterations (CNAs). The transcriptome was investigated in each of the components using RNA sequencing. Results:WES analysis of the AC and SCC components of one patient revealed a common trunk of 118 mutations, including driver mutations EGFR exon 19 deletion and TP53 p.192*, indicating a common clonal origin of the components and the presence of bona fide drivers in the common ancestor. AC shows more private mutations than SCC (234 vs 134). Potential drivers are private to AC included TP53 and AKT1 mutations, while TLX1 and TRBV5-1 mutations are restricted to SCC. AC and SCC have highly similar CNA profiles, suggesting that all CNAs are early evolutionary events of the ASC. Mutational signature of the truncal mutations is similar to that of the mutations private to AC, while mutations private to SCC showed a distinct pattern enriched in T>G, suggesting that SCC may have derived from an AC ancestor cell. Transcriptomic profiling shows that genes related to oxidative phosphorylation, fatty acid metabolism and peroxisome pathways are highly expressed in AC, in contrast to genes related to epithelial-mesenchymal-transition, hedgehog signaling and IL6-JAK-STAT3-signaling pathways in SCC. Conclusion:Macroscopic dissection and separate analysis of the histologically distinct components of an ASC of the lung demonstrated the clonal relatedness of the AC and SCC. The diverse phenotype of the components is associated with distinct genetic profiles and mutational signatures. Analysis of additional ASCs of the lung may reveal genetic and/or transcriptomic underpinnings of the phenotypes. Citation Format: Arthur Krause, Maria R. De Filippo, Thomas Lorber, Spasenija Savic, Salvatore Piscuoglio, Charlotte K. Ng, Lukas Bubendorf. Comprehensive analysis of the histologically distinct components of an adenosquamous carcinoma of the lung [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2515.