DNA methylation profiling of pituitary neuroendocrine tumors identifies distinct clinical and pathological subtypes based on epigenetic differentiation

ABSTRACT: Pituitary neuroendocrine tumors (PitNETs) are the most common intracranial neuroendocrine tumors. PitNETs are difficult to classify, and current recommendations include a large immunohistochemical panel to differentiate among 14 WHO-recognized categories. In this study, we analyzed 118 PitNETs to develop a clinico-molecular approach to classifying PitNETs. Comparison of clinical, immunohistochemical, and DNA methylation showed that PitNETs can be classified into distinct clinical and molecular subgroups. Unsupervised DNA methylation separated PitNETs into two major clusters. The first major cluster was composed of tumors currently labeled as gonadotrophs, which form a biologically distinct group of PitNETs characterized by clinical silence, weak hormonal expression on immunohistochemistry, and simple copy number profile. The second major cluster was composed of Corticotrophs and Pit1 lineage PitNETs, which could be further classified using DNA methylation into distinct subclusters that correspond to clinically active and silent tumors and consistent with degree of differentiation. Analysis of promoter methylation patterns correlates with lineage for corticotrophs and Pit1 lineage subtypes. However, the gonadotrophic genes do not show a distinct promoter methylation pattern in gonadotroph tumors compared to other lineages. Promoter of the NR5A1 gene, which encodes SF1, was hypermethylated across all PitNETs clinical and molecular subtypes including gonadotrophs with strong SF1 protein expression indicating alternative epigenetic regulation. These findings suggest that future classification of PitNETs may need to include DNA methylation for clinicopathological stratification.

ORGANISM(S): Homo sapiens

PROVIDER: GSE283928 | GEO | 2025/04/29

REPOSITORIES: GEO