Transcriptomic Classification of Pituitary Neuroendocrine Tumors Causing Acromegaly

Rymuza, Julia; Kober, Paulina; Rusetska, Natalia; Mossakowska, Beata Joanna; Maksymowicz, Maria; Nyc, Aleksandra; Baluszek, Szymon; Zieliński, Grzegorz; Kunicki, Jacek; Bujko, Mateusz

doi:10.3390/cells11233846

Cited by 7 publications

(21 citation statements)

References 47 publications

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“…A proportion of somatotroph PitNETs is characterized by high expression of GIPR, which plays an important role in the stimulation of GH secretion [18,19]. We previously found that GIPR-high somatotroph PitNETs belong to subtype 1, NR5A1-positive tumors [9], as is also confirmed by qRT-PCR (Fig. 5a).…”

Section: Role Of Dna Methylation Of Gipr Promotersupporting

confidence: 75%

“…Our data indicate that NR5A1-positive somatotroph tumors are those expressing GIPR [9]. The previous DNA methylation analysis of GIPR-high versus GIPRlow somatotroph PitNETs showed that they differ in methylation profiles.…”

Section: Discussionsupporting

confidence: 53%

“…NR5A1 encodes SF-1 transcription factor, which serves as a diagnostic marker of pituitary tumors of gonadotrophic lineage origin, but the expression of this gene in a subset of somatotroph tumors has been already reported by independent groups [9][10][11][12][13][14][15][16][17]. Gene expression analysis indicates that NR5A1-positive somatotroph PitNETs are a separate subtype of tumors causing acromegaly [9]. When comparing NR5A1-positive subtype 1 tumors with any other subtype, we found a difference in DNA methylation at NR5A1 gene.…”

Section: Discussionmentioning

confidence: 99%

“…NR5A1 encodes SF-1 transcription factor, an established marker of gonadotroph PitNETs. However, its expression was also observed in some somatotroph tumors [9][10][11][12][13][14][15][16][17]. The role of GIPR expression in the pathogenesis of these somatotroph PitNETs was also already determined [18,19].…”

Section: Introductionmentioning

confidence: 99%

“…Molecular subtype 2 somatotroph tumors are densely granulated, with a high frequency of GNAS mutations. They are of a smaller size and have high expression of favorable prognosis-related genes such as CDH1 and ESRP1 [9]. Among subtype 3 tumors, there are mainly sparsely granulated somatotroph PitNETs with low GNAS mutation incidence and a higher rate of invasive growth that corresponds to unfavorable outcomes, linked to high expression levels of particular tumor biology-related genes [9].…”

Section: Introductionmentioning

confidence: 99%

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DNA Methylation Pattern in Somatotroph Pituitary Neuroendocrine Tumors

Kober,

Rymuza,

Baluszek

et al. 2023

Neuroendocrinology

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Introduction: Growth hormone secretion by sporadic somatotroph neuroendocrine pituitary tumors (PitNETs) is a major cause of acromegaly. These tumors are relatively heterogenous in terms of histopathological and molecular features. Our previous transcriptomic profiling of somatotroph tumors revealed three distinct molecular subtypes. This study aimed to investigate the difference in DNA methylation patterns in subtypes of somatotroph PitNETs and its role in distinctive gene expression. Methods: Genome-wide DNA methylation was investigated in 48 somatotroph PitNETs with EPIC microarrays. Gene expression was assessed with RNAseq. Bisulfite pyrosequencing and qRT-PCR were used for verifying the results of DNA methylation and gene expression. Results: Clustering tumor samples based on methylation data reflected the transcriptome-related classification. Subtype 1 tumors are densely granulated without GNAS mutation, characterized by high expression of NR5A1 (SF-1) and GIPR. The expression of both genes is correlated with specific methylation of the gene body and promoter. This subtype has a lower methylation level of 5′ gene regions and CpG islands than the remaining tumors. Subtype 2 PitNETs are densely granulated and frequently GNAS-mutated, while those in subtype 3 are mainly sparsely granulated. Methylation/expression analysis indicates that ∼50% genes located in differentially methylated regions are those differentially expressed between tumor subtypes. Correlation analysis revealed DNA methylation-controlled genes, including CDKN1B, CCND2, EBF3, CDH4, CDH12, MGMT, STAT5A, PLXND1, PTPRE, and MMP16, and genes encoding ion channels and semaphorins. Conclusion: DNA methylation profiling confirmed the existence of three molecular subtypes of somatotroph PitNETs. High expression of NR5A1 and GIPR in subtype 1 tumors is correlated with specific methylation of both genes.

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Section: Role Of Dna Methylation Of Gipr Promotersupporting

confidence: 75%

Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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DNA Methylation Pattern in Somatotroph Pituitary Neuroendocrine Tumors

Kober,

Rymuza,

Baluszek

et al. 2023

Neuroendocrinology

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Pituitary neuroendocrine tumors with PIT1/SF1 co-expression show distinct clinicopathological and molecular features

Dottermusch,

Ryba,

Ricklefs

et al. 2024

Acta Neuropathol

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Pituitary neuroendocrine tumors (PitNETs) are classified according to cell lineage, which requires immunohistochemistry for adenohypophyseal hormones and the transcription factors (TFs) PIT1, SF1, and TPIT. According to the current WHO 2022 classification, PitNETs with co-expression of multiple TFs are termed “plurihormonal”. Previously, PIT1/SF1 co-expression was prevailingly reported in PitNETs, which otherwise correspond to the somatotroph lineage. However, little is known about such tumors and the WHO classification has not recognized their significance. We compiled an in-house case series of 100 tumors, previously diagnosed as somatotroph PitNETs. Following TF staining, histopathological features associated with PIT1/SF1 co-expression were assessed. Integration of in-house and publicly available sample data allowed for a meta-analysis of SF1-associated clinicopathological and molecular features across a total of 270 somatotroph PitNETs. The majority (74%, 52/70) of our densely granulated somatotroph PitNETs (DGST) unequivocally co-expressed PIT1 and SF1 (DGST-PIT1/SF1). None (0%, 0/30) of our sparsely granulated somatotroph PitNETs (SGST) stained positive for SF1 (SGST-PIT1). Among DGST, PIT1/SF1 co-expression was significantly associated with scarce FSH/LH expression and fewer fibrous bodies compared to DGST-PIT1. Integrated molecular analyses including publicly available samples confirmed that DGST-PIT1/SF1, DGST-PIT1 and SGST-PIT1 represent distinct tumor subtypes. Clinicopathological meta-analyses indicated that DGST-PIT1 respond more favorably towards treatment with somatostatin analogs compared to DGST-PIT1/SF1, while both these subtypes show an overall less aggressive clinical course than SGST-PIT1. In this study, we spotlight that DGST with co-expression of PIT1 and SF1 represent a common, yet underrecognized, distinct PitNET subtype. Our study questions the rationale of generally classifying such tumors as “plurihormonal”, and calls for a refinement of the WHO classification. We propose the term “somatogonadotroph PitNET”.

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