%0 Journal Article
%T Molecular subtypes of neuroendocrine carcinomas: A cross-tissue classification framework based on five transcriptional regulators.
%A Wang Z
%A Liu C
%A Zheng S
%A Yao Y
%A Wang S
%A Wang X
%A Yin E
%A Zeng Q
%A Zhang C
%A Zhang G
%A Tang W
%A Zheng B
%A Xue L
%A Wang Z
%A Feng X
%A Wang Y
%A Ying J
%A Xue Q
%A Sun N
%A He J
%J Cancer Cell
%V 42
%N 6
%D 2024 Jun 10
%M 38788718
%F 38.585
%R 10.1016/j.ccell.2024.05.002
%X 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.