Pangenomic Classification of Pituitary Neuroendocrine Tumors

Mario Neou; Chiara Villa; Roberta Armignacco; Anne Jouinot; Marie-Laure Raffin-Sanson; Amandine Septier; Franck Letourneur; Ségolène Diry; Marc Diedisheim; Brigitte Izac; Cassandra Gaspar; Karine Perlemoine; Victoria Verjus; Michèle Bernier; Anne Boulin; Jean-François Emile; Xavier Bertagna; Florence Jaffrezic; Denis Laloe; Bertrand Baussart; Jérôme Bertherat; Stephan Gaillard; Guillaume Assié

doi:10.1016/j.ccell.2019.11.002

Pangenomic Classification of Pituitary Neuroendocrine Tumors

Cancer Cell. 2020 Jan 13;37(1):123-134.e5. doi: 10.1016/j.ccell.2019.11.002. Epub 2019 Dec 26.

Authors

Mario Neou¹, Chiara Villa², Roberta Armignacco¹, Anne Jouinot¹, Marie-Laure Raffin-Sanson³, Amandine Septier¹, Franck Letourneur⁴, Ségolène Diry¹, Marc Diedisheim⁵, Brigitte Izac⁴, Cassandra Gaspar⁶, Karine Perlemoine¹, Victoria Verjus¹, Michèle Bernier⁷, Anne Boulin⁸, Jean-François Emile⁹, Xavier Bertagna¹⁰, Florence Jaffrezic¹¹, Denis Laloe¹¹, Bertrand Baussart¹², Jérôme Bertherat¹⁰, Stephan Gaillard¹², Guillaume Assié¹³

Affiliations

¹ INSERM U1016, Institut Cochin, 75014 Paris, France; CNRS UMR 8104, 75014 Paris, France; Université Paris Descartes-Université de Paris, 75006 Paris, France.
² INSERM U1016, Institut Cochin, 75014 Paris, France; CNRS UMR 8104, 75014 Paris, France; Université Paris Descartes-Université de Paris, 75006 Paris, France; Department of Pathological Cytology and Anatomy, Foch Hospital, 92151 Suresnes, France; Department of Endocrinology, Sart Tilman B35, 4000 Liège, Belgium.
³ Department of Endocrinology, Hôpital Ambroise Paré, Assistance Publique-Hôpitaux de Paris, 92100 Boulogne Billancourt, France; UE4340, Université de Versailles Saint-Quentin-en-Yvelines Montigny-le-Bretonneux, 78000 Versailles, France.
⁴ INSERM U1016, Institut Cochin, 75014 Paris, France; CNRS UMR 8104, 75014 Paris, France; Université Paris Descartes-Université de Paris, 75006 Paris, France; Plate-Forme Séquençage et Génomique (Genom'IC), INSERM U1016, Institut Cochin, 75014 Paris, France.
⁵ Department of Diabetology, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, 75014 Paris, France.
⁶ INSERM U1016, Institut Cochin, 75014 Paris, France; CNRS UMR 8104, 75014 Paris, France; Université Paris Descartes-Université de Paris, 75006 Paris, France; Sorbonne Université, Inserm, UMS PASS, Plateforme Post-génomique de la Pitié-Salpêtrière, P3S, 75013 Paris, France.
⁷ Department of Pathological Cytology and Anatomy, Foch Hospital, 92151 Suresnes, France.
⁸ Department of Diagnostic and Interventional Neuroradiology, Foch Hospital, 92151 Suresnes, France.
⁹ Department of Pathology, Ambroise Paré, Assistance Publique-Hôpitaux de Paris, 92100 Boulogne Billancourt, France.
¹⁰ INSERM U1016, Institut Cochin, 75014 Paris, France; CNRS UMR 8104, 75014 Paris, France; Université Paris Descartes-Université de Paris, 75006 Paris, France; Department of Endocrinology, Center for Rare Adrenal Diseases, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, 75014 Paris, France.
¹¹ INRA, UMR 1313 GABI, Université Paris Saclay, AgroParisTech, 78352 Jouy-en-Josas, France.
¹² Department of Neurosurgery, Foch Hospital, 92151 Suresnes, France.
¹³ INSERM U1016, Institut Cochin, 75014 Paris, France; CNRS UMR 8104, 75014 Paris, France; Université Paris Descartes-Université de Paris, 75006 Paris, France; Department of Endocrinology, Center for Rare Adrenal Diseases, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, 75014 Paris, France. Electronic address: guillaume.assie@aphp.fr.

PMID: 31883967
DOI: 10.1016/j.ccell.2019.11.002

Abstract

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.

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

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
Aged, 80 and over
Cell Lineage
Chromosome Aberrations
DNA Methylation
Endopeptidases / metabolism
Endosomal Sorting Complexes Required for Transport / metabolism
Epigenesis, Genetic
Epigenome
Exome
Female
Humans
Male
Middle Aged
Mutation
Neoplasm Invasiveness
Neuroendocrine Tumors / diagnosis*
Neuroendocrine Tumors / genetics*
Neuroendocrine Tumors / pathology
Pituitary Gland / metabolism
Pituitary Neoplasms / diagnosis*
Pituitary Neoplasms / genetics*
Pituitary Neoplasms / pathology
Prognosis
Transcriptome
Ubiquitin Thiolesterase / metabolism
Young Adult

Substances

Endosomal Sorting Complexes Required for Transport
Endopeptidases
USP8 protein, human
Ubiquitin Thiolesterase