DNA methylation profiling of pituitary neuroendocrine tumors identifies distinct clinical and pathological subtypes based on epigenetic differentiation.
Sarra Belakhoua, Varshini Vasudevaraja, Chanel Schroff, Kristyn Galbraith, Misha Movahed-Ezazi, Jonathan Serrano, Yiying Yang, Daniel Orringer, John G Golfinos, Chandra Sen, Donato Pacione, Nidhi Agrawal, Matija Snuderl
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Abstract
Background: Pituitary neuroendocrine tumors (PitNETs) are the most common intracranial neuroendocrine tumors. PitNETs can be challenging to classify, and current recommendations include a large immunohistochemical panel to differentiate among 14 WHO-recognized categories.
Methods: In this study, we analyzed clinical, immunohistochemical and DNA methylation data of 118 PitNETs to develop a clinico-molecular approach to classifying PitNETs and identify epigenetic classes.
Results: CNS DNA methylation classifier has an excellent performance in recognizing PitNETs and distinguishing the three lineages when the calibrated score is ≥0.3. Unsupervised DNA methylation analysis separated PitNETs into two major clusters. The first was composed of silent gonadotrophs, which form a biologically distinct group of PitNETs characterized by clinical silencing, 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 corresponded to clinically functioning and silent tumors and are consistent with transcription factor expression. Analysis of promoter methylation patterns correlated with lineage for corticotrophs and Pit1 lineage subtypes. However, the gonadotrophic genes did 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.
Conclusion: Our findings suggest that classification of PitNETs may benefit from DNA methylation for clinicopathological stratification.
期刊介绍：
Neuro-Oncology, the official journal of the Society for Neuro-Oncology, has been published monthly since January 2010. Affiliated with the Japan Society for Neuro-Oncology and the European Association of Neuro-Oncology, it is a global leader in the field.
The journal is committed to swiftly disseminating high-quality information across all areas of neuro-oncology. It features peer-reviewed articles, reviews, symposia on various topics, abstracts from annual meetings, and updates from neuro-oncology societies worldwide.
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