Comprehensive molecular portrait reveals genetic diversity and distinct molecular subtypes of small intestinal neuroendocrine tumors

Céline Patte, Roxane M. Pommier, Anthony Ferrari, Felicia Fei-Lei Chung, Maria Ouzounova, Pauline Moullé, Mathieu Richaud, Rita Khoueiry, Maëva Hervieu, Silvia Breusa, Marion Allio, Nicolas Rama, Laura Gérard, Valérie Hervieu, Gilles Poncet, Tanguy Fenouil, Vincent Cahais, Anne-Sophie Sertier, Anne Boland, Delphine Bacq-Daian, Benjamin Ducarouge, Julien C. Marie, Jean-François Deleuze, Alain Viari, Jean-Yves Scoazec, Colette Roche, Patrick Mehlen, Thomas Walter () and Benjamin Gibert ()
Additional contact information
Céline Patte: Cancer Research Center of Lyon
Roxane M. Pommier: Centre Léon Bérard
Anthony Ferrari: Centre Léon Bérard
Felicia Fei-Lei Chung: International Agency for Research on Cancer (IARC)
Maria Ouzounova: Cancer Research Center of Lyon
Pauline Moullé: Cancer Research Center of Lyon
Mathieu Richaud: Cancer Research Center of Lyon
Rita Khoueiry: International Agency for Research on Cancer (IARC)
Maëva Hervieu: Cancer Research Center of Lyon
Silvia Breusa: Cancer Research Center of Lyon
Marion Allio: Cancer Research Center of Lyon
Nicolas Rama: Cancer Research Center of Lyon
Laura Gérard: Cancer Research Center of Lyon
Valérie Hervieu: Cancer Research Center of Lyon
Gilles Poncet: Service de Chirurgie Digestive
Tanguy Fenouil: Cancer Research Center of Lyon
Vincent Cahais: International Agency for Research on Cancer (IARC)
Anne-Sophie Sertier: Centre Léon Bérard
Anne Boland: Centre National de Recherche en Génomique Humaine (CNRGH)
Delphine Bacq-Daian: Centre National de Recherche en Génomique Humaine (CNRGH)
Benjamin Ducarouge: Netris Pharma
Julien C. Marie: Equipe labellisée Ligue nationale contre le cancer, Cancer Research Center of Lyon
Jean-François Deleuze: Centre National de Recherche en Génomique Humaine (CNRGH)
Alain Viari: Centre Léon Bérard
Jean-Yves Scoazec: Gustave Roussy
Colette Roche: Cancer Research Center of Lyon
Patrick Mehlen: Cancer Research Center of Lyon
Thomas Walter: Cancer Research Center of Lyon
Benjamin Gibert: Cancer Research Center of Lyon

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-57305-8

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