Endocrine Abstracts

Corticotrope cells give arise to utmost aggressive and to very rare pituitary neoplasias, including pituitary carcinomas, Crooke’s cell adenomas (CCA), clinically non-functioning silent corticotrope adenomas (SCA) and the Cushing-provoking pituitary adenomas (CD). The molecular etiopathogenesis of these tumors are still poorly understood. Therefore, we carried out whole exome sequencing to better understand the full genomic landscape single nucleotide variants and copy number variations of the pituitary macroadenoma tumors from corticotrope lineage. Carcinomas show SNV in USP8, TP53, AURKA, EGFR, HSD3B1 and CDKN1A. Whereas in CCA SNV in HSD3B1 and CDKN1A where common however TP53 and AURKA were present in one each. HSD3B1 and CDKN1A SNV were present in all SCA, followed by EGFR and AURKA. They did not show USP8 SNV. As for the CD only one show USP8 SNV, corresponding to an Nelson syndrome tumor. All CD show TP53 and HSD3B1 SNV. None of the corticotrope tumors showed USP48, BRAF, BRG1 nor CABLES1 SNV. Functioning tumors including carcinoma and CD showed more CNV gains than the non-functioning tumors, carcinoma shares 10q11.22 amplification with benign adenomas, whereas 17q12 characterizes only benign adenomas. The theoretical evolutive development of the corticotrope carcinoma starting from the silent adenomas, if that’s the case, shows two main clades, the first and smallest, contain two SCA (2/3) and two CD (2/5), these four adenomas shared SNV profile, potentially indicating the genes needed to be altered to make a transition from silent to overt tumors. ATF7IP characterize this clade. The second and largest clade harbors the CCA (1/1), the carcinoma (1/1), one SCA (1/3) and three CD (3/5). Interestingly, in this clade the carcinoma showed a close relation to CCA and to a CD. This clade could represent the molecular alterations required to make the transition from overt adenoma to a carcinoma, or at least to a more aggressive tumor. In this clade there was clustered a Nelson syndrome CD and the carcinoma, which are very aggressive entities. MSH3 gene characterize this clade. Overall, pituitary carcinoma and CD showed more SNV and CNV genomic alterations compared against CCA and SCA.