Comprehensive molecular portrait reveals genetic diversity and distinct molecular subtypes of small intestinal neuroendocrine tumors
Small intestinal neuroendocrine tumors (siNETs) are rare bowel tumors arising from malignant enteroendocrine cells, which normally regulate digestion throughout the intestine. Though infrequent, their incidence is rising through better diagnosis, fostering research into their origin and treatment. To date, siNETs are considered to be a single entity and are clinically treated as such. Here, by performing a multi-omics analysis of siNETs, we unveil four distinct molecular groups with strong clinical relevance and provide a resource to study their origin and clinical features. Transcriptomic, genetic and DNA methylation profiles identify two groups linked to distinct enteroendocrine differentiation patterns, another with a strong immune phenotype, and the last with mesenchymal properties. This latter subtype displays the worst prognosis and resistance to treatments in line with infiltration of cancer-associated fibroblasts. These data provide insights into the origin and diversity of these rare diseases, in the hope of improving clinical research into their management.
Authors
- Silvia Breusa (ORCID: https://orcid.org/0000-0001-5094-8164)
- Thomas Walter (ORCID: https://orcid.org/0000-0002-4199-4561)
- Colette Roche (ORCID: https://orcid.org/0000-0003-1404-8040)
- Vincent Cahais (ORCID: https://orcid.org/0000-0001-5530-4368)
- Benjamin Gibert (ORCID: https://orcid.org/0000-0002-5295-3124)
- Céline Patte (ORCID: https://orcid.org/0000-0002-3292-5628)
- Julien C. Marie (ORCID: https://orcid.org/0000-0001-6713-7923)
- Felicia Fei‐Lei Chung (ORCID: https://orcid.org/0000-0003-1043-4948)
- Tanguy Fenouil (ORCID: https://orcid.org/0000-0002-2747-763X)
- Jean‐Yves Scoazec (ORCID: https://orcid.org/0000-0003-1604-6823)
- Jean‐François Deleuze (ORCID: https://orcid.org/0000-0002-5358-4463)
- Patrick Mehlen (ORCID: https://orcid.org/0000-0003-1743-5417)
- Delphine Daian (ORCID: https://orcid.org/0000-0002-6965-8244)
- Anne Boland (ORCID: https://orcid.org/0000-0001-8789-5676)
- Rita Khoueiry (ORCID: https://orcid.org/0000-0003-2089-4315)
- Laura Gérard (ORCID: https://orcid.org/0009-0005-9369-6389)
- Anne-Sophie Sertier (ORCID: https://orcid.org/0000-0001-7417-081X)
- Nicolas Rama (ORCID: https://orcid.org/0000-0003-1614-7755)
- Maëva Hervieu
- Maria Ouzounova (ORCID: https://orcid.org/0000-0001-8934-3461)
- Roxane M. Pommier (ORCID: https://orcid.org/0000-0002-5351-7367)
- Anthony Ferrari (ORCID: https://orcid.org/0009-0008-5386-5688)
- Mathieu Richaud (ORCID: https://orcid.org/0000-0002-7472-9019)
- Benjamin Ducarouge (ORCID: https://orcid.org/0000-0002-6701-0508)
- Marion Allio
- Pauline Moullé (ORCID: https://orcid.org/0000-0002-1566-1229)
- Alain Viari
- Valérie Hervieu
- Gilles Poncet
Institutions
- Université Claude Bernard Lyon 1 (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Université Paris-Saclay (FR)
- Institut Gustave Roussy (FR)
- Centre National de Recherche en Génomique Humaine (FR)
- Netris Pharma (France) (FR)
- Hospices Civils de Lyon (FR)
- Centre Léon Bérard (FR)
- Hôpital Edouard Herriot (FR)
- Centre de Recherche en Cancérologie de Lyon (FR)
- CEA Paris-Saclay (FR)
- Centre international de recherche sur le cancer (FR)
- Sunway University (MY)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-04
- DOI
- https://doi.org/10.1038/s41467-025-57305-8
- Citations
- 12
- Primary Topic
- Neuroendocrine Tumor Research Advances
- Type
- article
- Field-Weighted Citation Impact
- 16.25