Abstract
Pituitary neuroendocrine tumors (PitNETs) are common, generally benign tumors with complex clinical characteristics related to hormone hypersecretion and/or growing sellar tumor mass. PitNETs can be classified based on the expression pattern of anterior pituitary hormones and three main transcriptions factors (TF), SF1, PIT1 and TPIT that regulate differentiation of adenohypophysial cells. Here, we have extended this classification based on the global transcriptomics landscape using tumor tissue from a well-defined cohort comprising 51 PitNETs of different clinical and histological types. The molecular profiles were compared with current classification schemes based on immunohistochemistry. Our results identified three main clusters of PitNETs that were aligned with the main pituitary TFs expression patterns. Our analyses enabled further identification of specific genes and expression patterns, including both known and unknown genes, that could distinguish the three different classes of PitNETs. We conclude that the current classification of PitNETs based on the expression of SF1, PIT1 and TPIT reflects three distinct subtypes of PitNETs with different underlying biology and partly independent from the expression of corresponding hormones. The transcriptomic analysis reveals several potentially targetable tumor-driving genes with previously unknown role in pituitary tumorigenesis.
Highlights
Pituitary neuroendocrine tumors, traditionally designated as pituitary adenomas, represent a biologically heterogenous group of neoplasms of adenohypophysial cell origin [2, 27]
The transcriptomics data was obtained from RNA sequencing of fresh frozen tissue and normalized mRNA levels were determined for each sample, calculated as transcript per million (TPM) values
The results reveal three main clusters corresponding well to the expected categories of tumors based on the three main transcriptions factors (TF) (SF1, T-box family member 19 (TPIT) and pituitary transcription factor 1 (PIT1)), with the PIT1 cluster separated from the more closely related steroidogenic factor-1 (SF1) and TPIT clusters (Fig. 1a)
Summary
Traditionally designated as pituitary adenomas, represent a biologically heterogenous group of neoplasms of adenohypophysial cell origin [2, 27]. The pituitary cell lineages are defined by expression of anterior pituitary hormones and pituitary specific transcription factors (TFs): steroidogenic factor-1 (SF1), encoded by the NR5A1 gene, that regulates differentiation of gonadotroph cells producing folliculostimulating (FSH) and luteinizing (LH) hormone [1, 56], pituitary transcription factor 1 (PIT1), encoded by the POU1F1 gene, that determines the Tebani et al acta neuropathol commun (2021) 9:181 development of growth hormone (GH), prolactin (PRL) and thyroid stimulating hormone (TSH) producing cells [3, 23], and the T-box transcription factor TPIT, encoded by the TBX19 gene, responsible for the development of corticotroph cells that produce adrenocorticotroph hormone (ACTH), encoded by the POMC gene [19, 37]. The commonly used names for these pituitary transcription factors (SF1, PIT1 and TPIT) and corresponding hormones (FSH, LH, GH, PRL, TSH and ACTH) will be used throughout the manuscript for respective genes and gene transcripts
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