Integrating methylome and transcriptome signatures expands the molecular classification of the pituitary tumors
Creators: name: da Silva-Júnior, Rui Milton Patrício
name: Bueno, Ana Carolina
name: Martins, Clarissa Silva
name: Coelli-Lacchini, Fernanda
name: Ozaki, Jorge Guilherme Okanobo
name: de Almeida e Silva, Danillo Cunha
name: Marrero-Gutiérrez, Junier
name: Garcia-Peral, Carlos
name: Machado, Helio Rubens
name: dos Santos, Marcelo Volpon
name: Elias, Paula Lamparelli
name: Moreira, Ayrton Custódio
name: Colli, Leandro Machado
name: Vêncio, Ricardo Z. N.
name: Antonini, Sonir R
name: de Castro, Margaret
Publisher: name: Zenodo
Year: 2023
Subjects: GH- and -ACTH secreting pituitary tumors
non-functioning pituitary tumors
DNA methylation and RNA-seq signatures

description: <strong>Purpose</strong>: To explore pituitary tumors by methylome and transcriptome signatures in a heterogeneous ethnic population. <strong>Design</strong>: Retrospective cross-sectional study. <strong>Patients and Methods</strong>: Clinicopathological features, methylome, and transcriptome were evaluated in pituitary tumors from 77 patients (61% women, age: 12-72 years)followed due to functioning (FPT: GH-secreting n=18, ACTH-secreting n=14) and non-functioning pituitary tumors (NFPT, n=45) at Ribeirao Preto Medical School, University of Sao Paulo. <strong>Results</strong>: Unsupervised hierarchical clustering analysis (UHCA) of methylome (n=77) and transcriptome (n=65 out of 77) revealed three clusters each: one enriched by FPT, other by NFPT, and another by ACTH-secreting and NFPT. Comparison between each omics-derived cluster identified 3,568 and 5,994 differentially methylated and expressed genes, respectively, which were associated with each other, with tumor clinical presentation, and with 2017 and 2022 WHO classifications. UHCA considering 11 transcripts related to pituitary development/differentiation also supported three clusters: <em>POU1F1</em>-driven somatotroph, <em>TBX19</em>-driven corticotroph, and <em>NR5A1</em>-driven gonadotroph adenomas, with rare exceptions (<em>NR5A1</em> expressed in few GH-secreting and corticotroph-silent adenomas; <em>POU1F1</em> in few ACTH-secreting adenomas; and <em>TBX19</em> in few NFPTs). <strong>Conclusions</strong>: This large heterogenic ethnic Brazilian cohort confirms that integrated methylome and transcriptome signatures classify FPT and NFPT, which are associated with clinical presentation and tumor invasiveness. Moreover, the cluster NFPT/ACTH-secreting adenomas raises interest regarding tumor heterogeneity, supporting the challenge raised by the 2017 and 2022 WHO definitions regarding the discrepancy, in rare cases, between clinical presentation and pituitary lineage markers. Finally, making our data publicly available enables further studies to validate genes/pathways involved in pituitary tumor pathogenesis and prognosis.
description: Funding provided by: Fundação de Amparo à Pesquisa do Estado de São Paulo<br>Crossref Funder Registry ID: http://dx.doi.org/10.13039/501100001807<br>Award Number: 14/03989-6Funding provided by: Fundação de Amparo à Pesquisa do Estado de São Paulo<br>Crossref Funder Registry ID: http://dx.doi.org/10.13039/501100001807<br>Award Number: 19/00849-2Funding provided by: Fundação de Amparo à Pesquisa do Estado de São Paulo<br>Crossref Funder Registry ID: http://dx.doi.org/10.13039/501100001807<br>Award Number: 19/00860-6Funding provided by: Fundação de Amparo à Pesquisa do Estado de São Paulo<br>Crossref Funder Registry ID: http://dx.doi.org/10.13039/501100001807<br>Award Number: 20/03835-0Funding provided by: Fundação de Amparo à Pesquisa do Estado de São Paulo<br>Crossref Funder Registry ID: http://dx.doi.org/10.13039/501100001807<br>Award Number: 21/04368-9