Pangenomic Classification of Pituitary Neuroendocrine Tumors

Pituitary neuroendocrine tumors (PitNETs), are common, with five main histological subtypes: lactotroph, somatotroph, and thyrotroph (POU1F1/PIT1 lineage); corticotroph (TBX19/TPIT lineage); and gonadotroph (NR5A1/SF1 lineage). We report the first comprehensive pangenomic classification of PitNETs. PitNETs from PIT1 lineage showed an epigenetic signature of diffuse DNA hypomethylation, with transposable elements expression and chromosomal instability (except for GNAS-mutated somatotrophs). In TPIT lineage, corticotrophs were divided in three classes: the USP8-mutated with overt secretion, the USP8-wildtypes with increased invasiveness and increased epithelial-mesenchymal-transition, and the large silent tumors with gonadotroph trans-differentiation. Unexpected expression of gonadotroph markers was also found in GNAS-wildtype somatotrophs (SF1 expression), challenging the current definition of SF1/gonadotroph lineage. This classification improves our understanding and impacts clinical stratification of patients with PitNETs.