中国医学科学院和北京协和医学院Jie He和Nan Sun共同合作，近期取得重要工作进展。他们研究提出了神经内分泌癌的分子亚型：基于五种转录调节因子的跨组织分类框架。相关研究成果2024年5月23日在线发表于《癌细胞》杂志上。

据介绍，神经内分泌癌（NES）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的特性由于其稀有性和显著的组织间和组织内异质性而受到阻碍。

通过对来自31种不同组织的1000多个NEC的综合分析，研究人员揭示了它们与组织无关的融合，并进一步揭示了由不同转录调控因子驱动的分子分化。因此，全组织NEC可分为五种固有亚型，分别由ASCL1、NEUROD1、HNF4A、POU2F3和YAP1定义。对这些亚型进行了全面的描述，重点介绍了亚型特异性转录程序、基因组改变、演化轨迹、治疗脆弱性和临床病理表现。

新发现的以HNF4A为主的H亚型表现出胃肠道样特征、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，其中亚型的流行程度取决于环境，而环境是其表型差异的基础。

附：英文原文

Title: Molecular subtypes of neuroendocrine carcinomas: A cross-tissue classification framework based on five transcriptional regulators

Author: Zhanyu Wang, Chengming Liu, Sufei Zheng, Yuxin Yao, Sihui Wang, Xinfeng Wang, Enzhi Yin, Qingpeng Zeng, Chaoqi Zhang, Guochao Zhang, Wei Tang, Bo Zheng, Liyan Xue, Zhen Wang, Xiaoli Feng, Yan Wang, Jianming Ying, Qi Xue, Nan Sun, Jie He

Issue&Volume: 2024-05-23

Abstract: Neuroendocrine carcinomas (NECs) are extremely lethal malignancies that can ariseat almost any anatomic site. Characterization of NECs is hindered by their rarityand significant inter- and intra-tissue heterogeneity. Herein, through an integrativeanalysis of over 1,000 NECs originating from 31 various tissues, we reveal their tissue-independentconvergence and further unveil molecular divergence driven by distinct transcriptionalregulators. Pan-tissue NECs are therefore categorized into five intrinsic subtypesdefined by ASCL1, NEUROD1, HNF4A, POU2F3, and YAP1. A comprehensive portrait of these subtypes is depicted, highlighting subtype-specifictranscriptional programs, genomic alterations, evolution trajectories, therapeuticvulnerabilities, and clinicopathological presentations. Notably, the newly discoveredHNF4A-dominated subtype-H exhibits a gastrointestinal-like signature, wild-type RB1, unique neuroendocrine differentiation, poor chemotherapeutic response, and prevalentlarge-cell morphology. The proposal of uniform classification paradigm illuminates transcriptional basis of NEC heterogeneity and bridges the gap across different lineagesand cytomorphological variants, in which context-dependent prevalence of subtypesunderlies their phenotypic disparities.

DOI: 10.1016/j.ccell.2024.05.002

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00163-6