Nesrine Benanteur, Chiara Villa, Fabio Bioletto, Maria Francesca Birtolo, D. De Murat, Julien Masliah-Planchon, Victor Gravrand, Inès Lebib, Mounia Benkhellat, Robin Boëzennec, Stéphanie Allassonnière, Franck Letourneur, Y. Ruiz Martín, Fidéline Bonnet Serrano, Julian Jacob, Valentin Calugaru, Maxime Barat, Anthony Dohan, Jennifer Arrondeau, Olivier Huillard, Marie-Laure Raffin-Sanson, Jean François Emile, Gérald Raverot, Rossella Libé, Laurence Guignat, Cyril Garcia, L. Groussin, Xavier Bertagna, S. Gaillard, Jérôme Bertherat, Anne Jouinot, Bertrand Baussart, Guillaume Assié
BACKGROUND: Aggressive evolution of PitNETs is rare, metastatic spread 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 ≥40mm, 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 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 globally stable during the course of the disease, despite evolution towards 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 cohorts studies are needed to validate these molecular signatures and establish their prognostic value.