Genomic characterization of aggressiveness in pituitary neuroendocrine tumors

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.Aggressive tumors of the pituitary gland are rare. There is no clear clinical definition, and the prediction of the clinical course is limited. Can we define aggressiveness using molecular signatures? Here, we analyzed tumors from 206 patients using molecular, gene-based methods. We identified 2 molecular patterns linked to aggressiveness that were related to subsets of specific tumor types. These patterns include patterns of gene expression related to tumor growth, changes in DNA, and cancer-related mutations. Conversely, several subsets of tumors remain benign, also showing specific molecular patterns. These patterns remained stable during the course of the disease. Our findings provide a biological definition of aggressiveness that may improve risk assessment and guide treatment.