Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei, Taiwan.
Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Mod Pathol. 2024 Jan;37(1):100354. doi: 10.1016/j.modpat.2023.100354. Epub 2023 Oct 14.
Sclerosing pneumocytoma is a rare and distinct lung neoplasm whose histogenesis and molecular alterations are the subject of ongoing research. Our recent study revealed that AKT1 internal tandem duplications (ITD), point mutations, and short indels were present in almost all tested sclerosing pneumocytomas, suggesting that AKT1 mutations are a major driving oncogenic event in this tumor. Although the pathogenic role of AKT1 point mutations is well established, the significance of AKT1 ITD in oncogenesis remains largely unexplored. We conducted comprehensive genomic and transcriptomic analyses of sclerosing pneumocytoma to address this knowledge gap. RNA-sequencing data from 23 tumors and whole-exome sequencing data from 44 tumors were used to obtain insights into their genetic and transcriptomic profiles. Our analysis revealed a high degree of genetic and transcriptomic similarity between tumors carrying AKT1 ITD and those with AKT1 point mutations. Mutational signature analysis revealed COSMIC signatures 1 and 5 as the prevailing signatures of sclerosing pneumocytoma, associated with the spontaneous deamination of 5-methylcytosine and an unknown etiology, respectively. RNA-sequencing data analysis revealed that the sclerosing pneumocytoma gene expression profile is characterized by activation of the PI3K/AKT/mTOR pathway, which exhibits significant similarity between tumors harboring AKT1 ITD and those with AKT1 point mutations. Notably, an upregulation of SOX9, a transcription factor known for its involvement in fetal lung development, was observed in sclerosing pneumocytoma. Specifically, SOX9 expression was prominent in the round cell component, whereas it was relatively lower in the surface cell component of the tumor. To the best of our knowledge, this is the first comprehensive investigation of the genomic and transcriptomic characteristics of sclerosing pneumocytoma. Results of the present study provide insights into the molecular attributes of sclerosing pneumocytoma and a basis for future studies of this enigmatic tumor.
硬化性肺细胞瘤是一种罕见且独特的肺部肿瘤，其发生机制和分子改变是目前研究的主题。我们最近的研究表明，AKT1 内部串联重复（ITD）、点突变和短插入缺失存在于几乎所有测试的硬化性肺细胞瘤中，提示 AKT1 突变是该肿瘤的主要驱动致癌事件。虽然 AKT1 点突变的致病作用已得到充分证实，但 AKT1 ITD 在肿瘤发生中的意义在很大程度上仍未得到探索。我们对硬化性肺细胞瘤进行了全面的基因组和转录组分析，以解决这一知识空白。使用 23 个肿瘤的 RNA-seq 数据和 44 个肿瘤的全外显子组测序数据，深入了解它们的遗传和转录组特征。我们的分析揭示了携带 AKT1 ITD 的肿瘤和携带 AKT1 点突变的肿瘤之间具有高度的遗传和转录组相似性。突变特征分析显示，COS-MIC 特征 1 和 5 是硬化性肺细胞瘤的主要特征，分别与 5-甲基胞嘧啶的自发脱氨和未知病因有关。RNA-seq 数据分析表明，硬化性肺细胞瘤的基因表达谱特征是 PI3K/AKT/mTOR 通路的激活，携带 AKT1 ITD 的肿瘤和携带 AKT1 点突变的肿瘤之间存在显著相似性。值得注意的是，在硬化性肺细胞瘤中观察到转录因子 SOX9 的上调，SOX9 已知参与胎儿肺发育。具体而言，SOX9 表达在圆形细胞成分中较为明显，而在肿瘤的表面细胞成分中相对较低。据我们所知，这是对硬化性肺细胞瘤基因组和转录组特征的首次全面研究。本研究的结果深入了解了硬化性肺细胞瘤的分子特征，并为今后对这种神秘肿瘤的研究提供了基础。
