Pangenomic classification of pituitary neuroendocrine tumors

Mario Neou (1, 2, 3, 4) , Chiara Villa (1, 2, 3, 4, 5, 6) , Roberta Armignacco (1, 2, 3, 4) , A. Jouinot (1, 2, 3, 4) , Marie-Laure Raffin-Sanson (7, 8) , A. Septier (1, 2, 3, 4) , Franck Letourneur (1, 2, 3, 4) , Ségolène Diry (1, 2, 3, 4) , Marc Diedisheim (9) , Brigitte Izac (2, 3, 4, 1) , Cassandra Gaspar (2, 4, 10, 11, 12, 1) , Karine Perlemoine (1, 2, 3, 4) , Victoria Verjus (1, 2, 3, 4) , Michèle Bernier (13) , Anne Boulin (13) , Jean-François Emile (14) , Xavier Bertagna (2, 3, 4, 1) , Florence Jaffrezic (15, 16) , Denis Laloë (15, 16) , Bertrand Baussart (13) , Jérôme Bertherat (2, 3, 4, 1) , Stéphanie Gaillard (13) , Guillaume Assié (2, 3, 4, 1)

1 IC UM3 (UMR 8104 / U1016) - Institut Cochin
2 CNRS - Centre National de la Recherche Scientifique
3 UPD5 - Université Paris Descartes - Paris 5
4 UPCité - Université Paris Cité
5 Department of Pathological Cytology and Anatomy
6 Department of Endocrinology B 35
7 Hôpital Ambroise Paré, Department of Endocrinology
8 UVSQ - Université de Versailles Saint-Quentin-en-Yvelines
9 Hôpital Cochin [AP-HP]
10 PASS-P3S - Plateforme Post-génomique de la Pitié-Salpêtrière
11 INSERM - Institut National de la Santé et de la Recherche Médicale
12 PASS - Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé
13 Hôpital Foch [Suresnes]
14 Hôpital Ambroise Paré [AP-HP]
15 GABI - Génétique Animale et Biologie Intégrative
16 Université Paris Saclay (COmUE)

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 a comprehensive pangenomic classification of PitNETs. PitNETs from POU1F1/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 into three classes: the USP8-mutated with overt secretion, the USP8-wild-type with increased invasiveness and increased epithelial-mesenchymal transition, and the large silent tumors with gonadotroph transdifferentiation. Unexpected expression of gonadotroph markers was also found in GNAS-wild-type somatotrophs (SF1 expression), challenging the current definition of SF1/gonadotroph lineage. This classification improves our understanding and affects the clinical stratification of patients with PitNETs.

Mots clés: transcriptome; chromosome alterations; exome; genomic; methylome; miRNome; outcome; pituitary neuroendocrine tumors (PitNETs)

Domaines: Sciences du Vivant [q-bio]

Mario Neou, Chiara Villa, Roberta Armignacco, A. Jouinot, Marie-Laure Raffin-Sanson, et al.. Pangenomic classification of pituitary neuroendocrine tumors. Cancer Cell, 2020, 37 (1), pp.123-134. ⟨10.1016/j.ccell.2019.11.002⟩. ⟨hal-02441511⟩