Introduction: A subgroup of lung adenocarcinoma shows neuroendocrine differentiation and expression of achaete‐scute family bHLH transcription factor 1 (ASCL1), common to high‐grade neuroendocrine tumors, small‐cell lung cancer and large cell neuroendocrine carcinoma. Methods: The aim of this study was to characterize clinical and molecular features of ASCL1‐positive lung adenocarcinoma by using recent transcriptome profiling in multiple patient cohorts and genome‐wide epigenetic profiling including data from The Cancer Genome Atlas. Results: The ASCL1‐positive subtype of lung adenocarcinoma developed preferentially in current or former smokers and usually did not harbor EGFR mutations. In transcriptome profiling, this subtype overlapped with the recently proposed proximal‐proliferative molecular subtype. Gene expression profiling of ASCL1‐positive cases suggested generally poor immune cell infiltration and none of the tumors were positive for programmed cell death ligand 1 protein expression. Genome‐wide methylation analysis showed global DNA hypomethylation in ASCL1‐positive cases. ASCL1 was associated with super‐enhancers in ASCL1‐positive lung adenocarcinoma cells, and ASCL1 silencing suppressed other super‐enhancer‐associated genes, suggesting that ASCL1 acts as a master transcriptional regulator. This was further reinforced by the essential roles of ASCL1 in cell proliferation, survival, and cell cycle control. Conclusions: These results suggest that ASCL1 defines a subgroup of lung adenocarcinoma with distinct molecular features by driving super‐enhancer‐mediated transcriptional programs.

中文翻译：

---

ASCL1阳性肺腺癌转录组和表观基因组特征的综合分析

简介：肺腺癌亚组显示神经内分泌分化和 achaete-scute 家族 bHLH 转录因子 1 (ASCL1) 的表达，常见于高级神经内分泌肿瘤、小细胞肺癌和大细胞神经内分泌癌。方法：本研究的目的是通过在多个患者队列中使用最近的转录组分析和全基因组表观遗传分析（包括来自癌症基因组图谱的数据）来表征 ASCL1 阳性肺腺癌的临床和分子特征。结果：肺腺癌的 ASCL1 阳性亚型优先在当前或以前的吸烟者中发展，并且通常不携带 EGFR 突变。在转录组分析中，该亚型与最近提出的近端增殖分子亚型重叠。ASCL1 阳性病例的基因表达谱表明免疫细胞浸润普遍较差，并且没有一个肿瘤对程序性细胞死亡配体 1 蛋白表达呈阳性。全基因组甲基化分析显示 ASCL1 阳性病例中的整体 DNA 低甲基化。ASCL1 与 ASCL1 阳性肺腺癌细胞中的超增强子相关，而 ASCL1 沉默抑制了其他超增强子相关基因，表明 ASCL1 是主要的转录调节因子。ASCL1 在细胞增殖、存活和细胞周期控制中的重要作用进一步加强了这一点。结论：这些结果表明，ASCL1 通过驱动超增强子介导的转录程序定义了具有不同分子特征的肺腺癌亚组。