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 Daian, Benjamin Ducarouge, Julien C. Marie, Jean‐François Deleuze, Alain Viari, Jean‐Yves Scoazec, Colette Roche, Patrick Mehlen, Thomas Walter, Benjamin Gibert
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. Small intestinal neuroendocrine tumours (siNETs) are rare bowel tumors generally considered to be a single entity. Here, the authors perform a multiomics analysis of siNETs and reveal four distinct molecular groups with clinical relevance, including groups linked to differentiation patterns, immunity, and mesenchymal properties.