THU082 Longitudinal Multiomics Characterization Of Paired Primary And Recurrent Aggressive Pituitary Tumors From The Same Patient Reveals Genomic Stability And Transcriptomic And Epigenetic Heterogeneity With Metabolic Pathways Alterations
Authors: Taniguchi-Ponciano Keiko , Chavez-Santoscoy Alejandra , Hinojosa-Alvarez Silvia , Hernandez-Perez Jesus , Valenzuela-Perez Alejandra , Vela-Patiño Sandra , Andonegui-Elguera Sergio , Cano-Zaragoza Amayrani , Martinez-Mendoza Florencia , Kerbel Jacobo , Zhang Zidong , Smith Gregory , Rubenstein Aliza , Cheng Wan Sze , Mendelev Natalia , Amper Mary Anne S , Zamojski Michel , Zaslavsky Elena , Ruf-Zamojski Frederique Murielle , Sealfon Stuart C , Mercado Moises , Marrero-Rodríguez Daniel 
Published: October 2023

Abstract
Disclosure: K. Taniguchi-Ponciano: None. A. Chavez-Santoscoy: None. S. Hinojosa-Alvarez: None. J. Hernandez-Perez: None. A. Valenzuela-Perez: None. S. Vela-Patiño: None. S. Andonegui-Elguera: None. A. Cano-Zaragoza: None. F. Martinez-Mendoza: None. J. Kerbel: None. Z. Zhang: None. G. Smith: None. A. Rubenstein: None. W. Cheng: None. N. Mendelev: None. M. Amper: None. M. Zamojski: None. E. Zaslavsky: None. F.M. Ruf-Zamojski: None. S.C. Sealfon: None. M. Mercado: None. D. Marrero-Rodríguez: None.
Pituitary tumors (PT) represent 20% of all intracranial neoplasms. Some behave aggressively, growing rapidly and invading surrounding tissues, with high recurrence rates and are frequently resistant to conventional therapies. We performed exome and transcriptome sequencing, as well as methylation profiling of primary and recurrent PT of the same patient. The cohort consisted of patients with GH- and gonadotropin-producing PT and a patient with an ACTH carcinoma. We sought genome evolution as well as transcriptomic and methylomic changes trough time, trying to identify molecular markers of recurrence. We performed scRNAseq to identify tumor cell populations. Compared to the primary PT, recurrent lesions showed less than 5% genomic changes in the SNV profile. The gonadotrophin-PT did not show common variants between patients or between primary and recurrent lesions. The ACTH-carcinoma showed USP8, TP53 and EGFR variants in both tumor samples, but no genomic changes between tumors despite a Ki67 of 80% in the recurrent lesion. A GH-tumor showed an AIP variant with high genetic heterogeneity. No CNV between the primary and recurrent tumors were observed. Regardless of their lineage, all PT showed different degrees of transcriptomic and methylomic heterogeneity between the primary and the recurrent lesions. Primary and recurrent tumors clustered separately from each other but together among themselves. Interestingly the differentially expressed and methylated genes in gonadotropin-producing PT are related to fatty acid biosynthesis and metabolism, GPI-anchor biosynthesis, and other metabolic pathways. ACTH-carcinoma differs significantly from the silent corticotrope in gene expression and methylation patterns. The ACTH-carcinoma showed alteration in N-Glycan biosynthesis, glycerophospholipid metabolism, purine and pyrimidine metabolism, whereas the silent corticotrope showed one carbon pool by folate, inositol phosphate metabolism, carbohydrate digestion and absorption and biosynthesis of unsaturated fatty acids. The GH-tumor showed alteration in pyruvate metabolism, propanoate metabolism, insulin secretion, and aldosterone synthesis and secretion. Our results suggest that there are several clones conforming a PT and some of them remain after surgical resection and can re-grow, this was confirmed by our scRNAseq analysis and immunofluorescence assays. We conclude that PT are genomically stable trough time, indicating that mechanisms other than somatic mutations are involved in pituitary tumorigenesis and that their biology could be driven by transcriptomically and epigenetically heterogeneous clones within the tumor itself.
Presentation: Thursday, June 15, 2023