An Integrative RNA Spliceosomic Landscape of Pancreatic Neuroendocrine Tumors Identifies Clinically Relevant Molecular Subgroups
Abstract
Alterations in alternative splicing are emerging as a novel cancer hallmark, offering new insights into tumor biology. However, integrative analyses of splicing are still scarce, particularly in rare cancers like pancreatic neuroendocrine tumors (PanNETs), whose striking heterogeneity complicates patient diagnosis and treatment. Here, we provide the first comprehensive characterization of the RNA splicing landscape in PanNETs through integrative analysis of RNA-seq data from 174 tumor samples. We identified three robust spliceosomic groups (SPN1, SPN2, SPN3) each associated with unique clinical and molecular characteristics. SPN1 displayed intermediate clinical behavior alongside enhanced mTOR signaling; SPN2 was characterized by a less secretory phenotype, enrichment in alpha-cell markers and somatostatin receptors, increased metastasis, and frequent mutations in MEN1 and DAXX/ATRX genes; in contrast, SPN3 was composed mainly by low grade tumors with beta-cell marker expression and the lowest mutational rate, yet it also contained all the highly proliferative neoplasms. Moreover, each group had a specific alternative splicing events signature, revealing an unprecedented discovery: the association between the expression profile of the splicing machinery and its product, the splicing variants. We provide a detailed characterization of the molecular and functional consequences of the splice variants defining each of the spliceosomic groups. These findings underscore the previously unrecognized yet significant impact of RNA splicing on PanNET heterogeneity and suggest that detailed splicing profiles could serve as valuable tools for identifying novel biomarkers and therapeutic targets. Thus, beyond providing crucial insights into PanNET molecular biology, our study offers a foundation for future studies exploring personalized therapeutic strategies based on splicing features.
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BibTeX
@article{blazquezencinas2026integrative,
title = {{An Integrative RNA Spliceosomic Landscape of Pancreatic Neuroendocrine Tumors Identifies Clinically Relevant Molecular Subgroups}},
author = {Ricardo Blázquez-Encinas and Víctor García-Vioque and Andrea Mafficini and Luca Landoni and Daniel Ruiz-Palacios and Laura Gutiérrez-Camacho and María Trinidad Moreno-Montilla and Nicolas Alcala and Sebastián Ventura and Eduardo Eyras and Salvatore Paiella and Roberto Salvia and Vita Rovite and Matthieu Foll and Claudio Luchini and Lynnette Fernandez-Cuesta and Rita T. Lawlor and Aldo Scarpa and Alejandro Ibáñez-Costa and Sergio Pedraza-Arevalo and Justo P. Castaño},
journal = {Endocrine Pathology},
year = {2026},
month = oct,
doi = {10.1007/s12022-026-09923-1},
url = {https://hal.science/hal-05842061v1},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - An Integrative RNA Spliceosomic Landscape of Pancreatic Neuroendocrine Tumors Identifies Clinically Relevant Molecular Subgroups
AU - Ricardo Blázquez-Encinas
AU - Víctor García-Vioque
AU - Andrea Mafficini
AU - Luca Landoni
AU - Daniel Ruiz-Palacios
AU - Laura Gutiérrez-Camacho
AU - María Trinidad Moreno-Montilla
AU - Nicolas Alcala
AU - Sebastián Ventura
AU - Eduardo Eyras
AU - Salvatore Paiella
AU - Roberto Salvia
AU - Vita Rovite
AU - Matthieu Foll
AU - Claudio Luchini
AU - Lynnette Fernandez-Cuesta
AU - Rita T. Lawlor
AU - Aldo Scarpa
AU - Alejandro Ibáñez-Costa
AU - Sergio Pedraza-Arevalo
AU - Justo P. Castaño
PY - 2026
DA - 2026/10/28
JO - Endocrine Pathology
DO - 10.1007/s12022-026-09923-1
UR - https://hal.science/hal-05842061v1
AB - Alterations in alternative splicing are emerging as a novel cancer hallmark, offering new insights into tumor biology. However, integrative analyses of splicing are still scarce, particularly in rare cancers like pancreatic neuroendocrine tumors (PanNETs), whose striking heterogeneity complicates patient diagnosis and treatment. Here, we provide the first comprehensive characterization of the RNA splicing landscape in PanNETs through integrative analysis of RNA-seq data from 174 tumor samples. We identified three robust spliceosomic groups (SPN1, SPN2, SPN3) each associated with unique clinical and molecular characteristics. SPN1 displayed intermediate clinical behavior alongside enhanced mTOR signaling; SPN2 was characterized by a less secretory phenotype, enrichment in alpha-cell markers and somatostatin receptors, increased metastasis, and frequent mutations in MEN1 and DAXX/ATRX genes; in contrast, SPN3 was composed mainly by low grade tumors with beta-cell marker expression and the lowest mutational rate, yet it also contained all the highly proliferative neoplasms. Moreover, each group had a specific alternative splicing events signature, revealing an unprecedented discovery: the association between the expression profile of the splicing machinery and its product, the splicing variants. We provide a detailed characterization of the molecular and functional consequences of the splice variants defining each of the spliceosomic groups. These findings underscore the previously unrecognized yet significant impact of RNA splicing on PanNET heterogeneity and suggest that detailed splicing profiles could serve as valuable tools for identifying novel biomarkers and therapeutic targets. Thus, beyond providing crucial insights into PanNET molecular biology, our study offers a foundation for future studies exploring personalized therapeutic strategies based on splicing features.
SN - 1046-3976
ER -