Loss of alveolar type II epithelial and endothelial cell lineages in invasive mucinous adenocarcinoma of the lung (IMA)

Background: Invasive mucinous adenocarcinoma of the lung (IMA) is pathologically characterized as lung tumor cells with goblet cell morphology containing abundant intracytoplasmic mucin. IMA has been reported to account for 2-10% of lung adenocarcinomas. Genetically, the majority of IMA harbor KRAS mutations. Recently, by analyzing RNA-seq data using human IMA cases, we reported mucus-related genes specifically expressed in IMA, which includes MUC5AC, MUC5B, MUC3, SPDEF, FOXA3 and HNF4 (Guo, Tomoshige et al., 2017). Notably, immunohistochemical analyses have determined that NKX2-1 (also known as TTF-1) is reduced in IMA (Travis et al., 2011); however, other than NKX2-1, genes reduced in IMA compared to normal lungs have not been determined. Methods: In order to further understand the demographic occurrence of IMA, we surveyed the clinical records at the University of Cincinnati College of Medicine in the U.S. and Nagasaki University of School of Medicine in Japan. Genes reduced in IMA compared to normal lungs were identified using the RNA-seq datasets as we have previously reported (Guo, Tomoshige et al., 2017). Using single-cell and sorted RNA-seq datasets (LGEA; Du et al., 2017), genes were further categorized into groups that define different cell types that exist in normal lungs. Results: IMA occurred in 4.6% (3/65 cases in 2017) and 1.9% (2/105 cases in 2017) of lung adenocarcinomas at the University of Cincinnati College of Medicine and Nagasaki University of School of Medicine, respectively. Importantly, analysis using normal lung cell type specification markers obtained from the single-cell and sorted RNA-seq datasets identified that genes that define alveolar type II epithelial cells (e.g., SFTPC and ABCA3) and endothelial cells (e.g., FOXF1 and SOX17) were significantly reduced in IMA compared to normal lungs. Conclusion: IMA comprises mucus-producing goblet cell lineage populations devoid of alveolar type II epithelial and endothelial cell-lineage populations, suggesting a unique tumor microenvironment distinct from other lung adenocarcinomas. Citation Format: Koichi Tomoshige, Minzhe Guo, Tomoshi Tsuchiya, Iris Fink-Baldauf, Takeshi Nagayasu, Kelsey Dillehay McKillip, Yutaka Maeda. Loss of alveolar type II epithelial and endothelial cell lineages in invasive mucinous adenocarcinoma of the lung (IMA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3675.