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Molecular subtypes of neuroendocrine carcinomas: A cross-tissue classification framework based on five
Zhanyu Wang1, Chengming Liu1, Sufei Zheng2
1Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China; State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China.
Abstract:
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.
Insights
Neuroendocrine carcinomas (NECs) are classified into five subtypes based on key regulators like ASCL1 and NEUROD1. This new classification reveals subtype-specific traits and therapeutic vulnerabilities in these rare cancers.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Neuroendocrine carcinomas (NECs) are aggressive, rare malignancies with diverse origins.
- Heterogeneity within and between NEC tissues complicates characterization and treatment.
Purpose of the Study:
- To integrate analyses of over 1,000 NECs from 31 tissues.
- To define intrinsic subtypes of pan-tissue NECs based on molecular drivers.
- To characterize subtype-specific features, including transcriptional programs, genomic alterations, and therapeutic vulnerabilities.
Main Methods:
- Integrative analysis of multi-tissue NEC genomic and transcriptomic data.
- Identification of key transcriptional regulators defining NEC subtypes.
- Comprehensive profiling of identified subtypes.
Main Results:
- NECs exhibit tissue-independent convergence and molecular divergence driven by distinct transcriptional regulators.
- Five intrinsic NEC subtypes were defined: ASCL1, NEUROD1, HNF4A, POU2F3, and YAP1.
- A novel HNF4A-dominated subtype (H) shows gastrointestinal features, wild-type RB1, unique differentiation, poor response to chemotherapy, and large-cell morphology.
Conclusions:
- A unified classification paradigm for NECs based on transcriptional regulators.
- Illuminates the molecular basis of NEC heterogeneity across lineages and cytomorphologies.
- Highlights context-dependent subtype prevalence and phenotypic disparities, guiding future research and therapeutic strategies.
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