Genetic and epigenetic characterization of posterior pituitary tumors
Creators: name: Schmid, Simone
name: Solomon, David A.
name: Perez, Eilis
name: Thieme, Anne
name: Kleinschmidt-DeMasters, Bette K.
name: Giannini, Caterina
name: Reinhardt, Annekathrin
name: Asa, Sylvia L.
name: Mete, Ozgur
name: Stichel, Damian
name: Siewert, Christin
name: Dittmayer, Carsten
name: Hasselblatt, Martin
name: Paulus, Werner
name: Nagel, Christoph
name: Harter, Patrick N.
name: Schittenhelm, Jens
name: Honegger, Jürgen
name: Rushing, Elisabeth
name: Coras, Roland
name: Pfister, Stefan M.
name: Buslei, Rolf
name: Koch, Arend
name: Perry, Arie
name: Jones, David T. W.
name: Deimling, Andreas Von
name: Capper, David
name: Lopes, M. Beatriz
Publisher: name: Charité - Universitätsmedizin Berlin
Year: 2021
Subjects: subject: Pituicytoma
subject: Spindle cell oncocytoma
subject: Granular cell tumor
subject: Posterior pituitary gland neoplasms
subject: Molecular neuropathology
subject: Brain tumor
subject: 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit

description: Pituicytoma (PITUI), granular cell tumor (GCT), and spindle cell oncocytoma (SCO) are rare tumors of the posterior pituitary. Histologically, they may be challenging to distinguish and have been proposed to represent a histological spectrum of a single entity. We performed targeted next-generation sequencing, DNA methylation profiling, and copy number analysis on 47 tumors (14 PITUI; 12 GCT; 21 SCO) to investigate molecular features and explore possibilities of clinically meaningful tumor subclassification. We detected two main epigenomic subgroups by unsupervised clustering of DNA methylation data, though the overall methylation differences were subtle. The largest group (n = 23) contained most PITUIs and a subset of SCOs and was enriched for pathogenic mutations within genes in the MAPK/PI3K pathways (12/17 [71%] of sequenced tumors: FGFR1 (3), HRAS (3), BRAF (2), NF1 (2), CBL (1), MAP2K2 (1), PTEN (1)) and two with accompanying TERT promoter mutation. The second group (n = 16) contained most GCTs and a subset of SCOs, all of which mostly lacked identifiable genetic drivers. Outcome analysis demonstrated that the presence of chromosomal imbalances was significantly associated with reduced progression-free survival especially within the combined PITUI and SCO group (p = 0.031). In summary, we observed only subtle DNA methylation differences between posterior pituitary tumors, indicating that these tumors may be best classified as subtypes of a single entity. Nevertheless, our data indicate differences in mutation patterns and clinical outcome. For a clinically meaningful subclassification, we propose a combined histo-molecular approach into three subtypes: one subtype is defined by granular cell histology, scarcity of identifiable oncogenic mutations, and favorable outcome. The other two subtypes have either SCO or PITUI histology but are segregated by chromosomal copy number profile into a favorable group (no copy number changes) and a less favorable group (copy number imbalances present). Both of the latter groups have recurrent MAPK/PI3K genetic alterations that represent potential therapeutic targets.