Genomic characterization of aggressiveness in pituitary neuroendocrine tumors
Abstract
BACKGROUND: Aggressive evolution of PitNETs is rare; metastatic spread is even more. Defining aggressiveness and malignancy is challenging, subsequently hard to predict, and to understand. The aim was to provide a molecular definition of aggressiveness using genomic approaches. METHODS: PitNETs from 206 patients were included. Associations between 9 clinicopathological features of aggressiveness and PitNETs' omics were explored. Omics included transcriptome, DNA methylation, chromosomal alterations, and mutations. Clonal tumor evolution was monitored in 7 patients. RESULTS: Among the 9 clinicopathological features of aggressiveness, only rapid progression, progression after radiotherapy, Ki67/MIB1 proliferation index ≥10%, temozolomide treatment, metastases, and specific death were associated with specific omics signatures, while tumour maximal diameter ≥40 mm, cavernous, and sphenoid invasion were not. The omic signatures associated with these features of aggressiveness overlapped but remained distinct between corticotroph and mammo-somato-thyrotroph lineages. For each lineage, a common signature of aggressiveness was identified, associating a proliferative transcriptome signature and DNA hypermethylation. Alterations in specific genes were associated with aggressive features, including a novel PitNET gene, LRP1B, and known cancer genes (TP53, CDKN2A), while USP8 and GNAS alterations were not. Integration of gene alterations with methylome and transcriptome signatures isolated a subset of molecularly aggressive PitNETs. Molecular signatures were stable during the course of the disease, despite evolution toward aggressiveness and potential clonal divergence. CONCLUSION: This systematic analysis of clinicopathological features of aggressiveness using an integrated multiomic approach establishes a histomolecular definition of aggressiveness in PitNETs. Prospective cohort studies are needed to validate these molecular signatures and establish their prognostic value.
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BibTeX
@article{benanteur2026genomic,
title = {{Genomic characterization of aggressiveness in pituitary neuroendocrine tumors}},
author = {Nesrine Benanteur and Chiara Villa and Fabio Bioletto and Maria Francesca Birtolo and Daniel de Murat and Julien Masliah-Planchon and Victor Gravrand and Inès Lebib and Mounia Benkhellat and Robin Boezennec and Stéphanie Allassonnière and Franck Letourneur and Yoann Martin and Fidéline Bonnet Serrano and Julian Jacob and Valentin Calugaru and Maxime Barat and Anthony Dohan and Jennifer Arrondeau and Olivier Huillard and Marie-Laure Raffin-Sanson and Jean François Emile and Gérald Raverot and Rossella Libé and Laurence Guignat and Cyril Garcia and Lionel Groussin and Xavier Bertagna and Stephan Gaillard and Jérôme Bertherat and Anne Jouinot and Bertrand Baussart and Guillaume Assié},
journal = {Neuro-Oncology},
year = {2026},
month = nov,
doi = {10.1093/neuonc/noag074},
url = {https://hal.science/hal-05851595v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Genomic characterization of aggressiveness in pituitary neuroendocrine tumors
AU - Nesrine Benanteur
AU - Chiara Villa
AU - Fabio Bioletto
AU - Maria Francesca Birtolo
AU - Daniel de Murat
AU - Julien Masliah-Planchon
AU - Victor Gravrand
AU - Inès Lebib
AU - Mounia Benkhellat
AU - Robin Boezennec
AU - Stéphanie Allassonnière
AU - Franck Letourneur
AU - Yoann Martin
AU - Fidéline Bonnet Serrano
AU - Julian Jacob
AU - Valentin Calugaru
AU - Maxime Barat
AU - Anthony Dohan
AU - Jennifer Arrondeau
AU - Olivier Huillard
AU - Marie-Laure Raffin-Sanson
AU - Jean François Emile
AU - Gérald Raverot
AU - Rossella Libé
AU - Laurence Guignat
AU - Cyril Garcia
AU - Lionel Groussin
AU - Xavier Bertagna
AU - Stephan Gaillard
AU - Jérôme Bertherat
AU - Anne Jouinot
AU - Bertrand Baussart
AU - Guillaume Assié
PY - 2026
DA - 2026/11/04
JO - Neuro-Oncology
DO - 10.1093/neuonc/noag074
UR - https://hal.science/hal-05851595v1
AB - BACKGROUND: Aggressive evolution of PitNETs is rare; metastatic spread is even more. Defining aggressiveness and malignancy is challenging, subsequently hard to predict, and to understand. The aim was to provide a molecular definition of aggressiveness using genomic approaches. METHODS: PitNETs from 206 patients were included. Associations between 9 clinicopathological features of aggressiveness and PitNETs' omics were explored. Omics included transcriptome, DNA methylation, chromosomal alterations, and mutations. Clonal tumor evolution was monitored in 7 patients. RESULTS: Among the 9 clinicopathological features of aggressiveness, only rapid progression, progression after radiotherapy, Ki67/MIB1 proliferation index ≥10%, temozolomide treatment, metastases, and specific death were associated with specific omics signatures, while tumour maximal diameter ≥40 mm, cavernous, and sphenoid invasion were not. The omic signatures associated with these features of aggressiveness overlapped but remained distinct between corticotroph and mammo-somato-thyrotroph lineages. For each lineage, a common signature of aggressiveness was identified, associating a proliferative transcriptome signature and DNA hypermethylation. Alterations in specific genes were associated with aggressive features, including a novel PitNET gene, LRP1B, and known cancer genes (TP53, CDKN2A), while USP8 and GNAS alterations were not. Integration of gene alterations with methylome and transcriptome signatures isolated a subset of molecularly aggressive PitNETs. Molecular signatures were stable during the course of the disease, despite evolution toward aggressiveness and potential clonal divergence. CONCLUSION: This systematic analysis of clinicopathological features of aggressiveness using an integrated multiomic approach establishes a histomolecular definition of aggressiveness in PitNETs. Prospective cohort studies are needed to validate these molecular signatures and establish their prognostic value.
SN - 1522-8517
SN - 1523-5866
ER -