Genomic characterization of aggressiveness in pituitary neuroendocrine tumors.
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Benanteur Nesrine, Villa Chiara, Bioletto Fabio, Birtolo Maria Francesca, De Murat Daniel, Masliah-Planchon Julien, Gravrand Victor, Lebib Inès, Benkhellat Mounia, Boezennec Robin, Allassonnière Stéphanie, Letourneur Franck, Martin Yoann, Bonnet Serrano Fidéline, Jacob Julian, Calugaru Valentin, Barat Maxime, Dohan Anthony, Arrondeau Jennifer, Huillard Olivier, Raffin-Sanson Marie-Laure, Emile Jean François, Raverot Gérald, Libé Rossella, Guignat Laurence, Garcia Cyril, Groussin Lionel, Bertagna Xavier, Gaillard Stephan, Bertherat Jérôme, Jouinot Anne, Baussart Bertrand, Assié Guillaume
Аннотация
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.