Integrating methylome and transcriptome signatures expands the molecular classification of the pituitary tumors

Purpose: To explore pituitary
tumors by methylome and transcriptome signatures in a
heterogeneous ethnic population.  Design: Retrospective
cross-sectional study. Patients and Methods: 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. 
Results: 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: POU1F1-driven
somatotroph, TBX19-driven corticotroph,
and NR5A1-driven gonadotroph adenomas, with rare exceptions
(NR5A1 expressed in few GH-secreting and corticotroph-silent
adenomas; POU1F1 in few ACTH-secreting adenomas;
and TBX19 in few NFPTs).  Conclusions: 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.