MON-LB081 Pituitary Adenomas: A Pan-genomic Classification

Pituitary adenomas are now called neuroendocrine tumors (PitNETs). Histological type, secretion, invasion and growth speed vary. A World Health Organization (WHO) histo-prognostic classification was released in 2017. Pituitary tumorigenesis is largely unexplained. Rare germline mutations (MENIN, AIP), and common somatic mutations in GNAS and USP8 are reported. Recently, genomic analyses have been reported. Yet, driver genes and pathways remain to be fully identified, as well as a comprehensive view of omics in the different subtypes of PitNETs Aim: To provide a genomic unbiased classification of PitNETs Methods: A clinical, histological and genomic characterization of 134 PitNETs of all subtypes was performed, combining exome, RNA and miRNA sequencing, SNP array and methylation array. Unsupervised classifications were generated. Results: Median somatic mutation rate was 95, mainly C>T belonging to “signature 1” signature. No difference was observed between histo-types. Only GNAS and USP8 presented >5% mutations. Three chromosome alteration profiles were identified: extended losses, “quiet” profiles, and extended gains. Gonadotroph and silent corticotroph were mainly “quiet”. Chromosomal alterations were not related to aggressiveness. MiRnome and methylome were associated with PitNETs histological type and secretion (chi2 p <10-18). Especially, PitNETs from Pit1 lineage (lacto-, thyreo- and somatotroph) showed diffuse DNA hypomethylation. Hypomethylation was correlated with genomic instability (correlation coef: 0.4) Unsupervised transcriptome classification revealed 6 groups, associated with histotype and secretion (chi2 p<10-59), with four noticeable discrepancies compared to WHO2017 classification: « null-cells » were mixed with gonadotroph PitNETs ; silent corticotroph fell apart from overt Cushing PitNETs; 5/8 sparsely granulated somatotroph were grouped with thyreotroph and PIT1 plurihormonal PitNETs; lactotroph were distinct from mixed GH-PRL and somatotroph PitNETs. USP8 and GNAS mutations formed specific homogeneous subgroups. Silent corticotroph and gonadotroph shared a common gonadotroph signature. Conclusion: This genomic study unravels important new aspects of PitNETs biology. Mainly: - DNA hypomethylation and chromosomal instability of PitNETs of the Pit1 lineage, suggesting that Pit1 differentiation may induce chromatin opening, with subsequent genome instability. - A specific molecular signature of sparsely granulated somatotroph PitNETs, which may help to better understand and predict resistance to somatostatin analogues. - Silent corticotroph PitNETs combine corticotroph and gonadotroph differentiation signatures. This genomic classification of PitNETs supports the importance of pituitary lineage in pituitary tumorigenesis, and proposes a first robust and unbiased classification based on tumor biology. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.