神经内分泌癌（NEC）是一种极其致命的恶性肿瘤，几乎可以发生在任何解剖部位。 NEC 的稀有性和显着的组织间和组织内异质性阻碍了 NEC 的表征。在此，通过对来自 31 个不同组织的 1,000 多个 NEC 进行综合分析，我们揭示了它们与组织无关的趋同，并进一步揭示了由不同转录调节因子驱动的分子分歧。因此，泛组织 NEC 被分为 ASCL1、NEUROD1、HNF4A、POU2F3 和 YAP1 定义的五种内在亚型。描绘了这些亚型的全面概况，突出显示了亚型特异性转录程序、基因组改变、进化轨迹、治疗漏洞和临床病理学表现。值得注意的是，新发现的 HNF4A 主导的 H 亚型表现出类似胃肠道的特征、野生型 RB1、独特的神经内分泌分化、较差的化疗反应和普遍的大细胞形态。统一分类范式的提出阐明了 NEC 异质性的转录基础，并弥合了不同谱系和细胞形态变异之间的差距，其中亚型的背景依赖性流行率是其表型差异的基础。版权所有 © 2024 Elsevier Inc. 保留所有权利。

Neuroendocrine carcinomas (NECs) are extremely lethal malignancies that can arise at almost any anatomic site. Characterization of NECs is hindered by their rarity and significant inter- and intra-tissue heterogeneity. Herein, through an integrative analysis of over 1,000 NECs originating from 31 various tissues, we reveal their tissue-independent convergence and further unveil molecular divergence driven by distinct transcriptional regulators. Pan-tissue NECs are therefore categorized into five intrinsic subtypes defined by ASCL1, NEUROD1, HNF4A, POU2F3, and YAP1. A comprehensive portrait of these subtypes is depicted, highlighting subtype-specific transcriptional programs, genomic alterations, evolution trajectories, therapeutic vulnerabilities, and clinicopathological presentations. Notably, the newly discovered HNF4A-dominated subtype-H exhibits a gastrointestinal-like signature, wild-type RB1, unique neuroendocrine differentiation, poor chemotherapeutic response, and prevalent large-cell morphology. The proposal of uniform classification paradigm illuminates transcriptional basis of NEC heterogeneity and bridges the gap across different lineages and cytomorphological variants, in which context-dependent prevalence of subtypes underlies their phenotypic disparities.Copyright © 2024 Elsevier Inc. All rights reserved.