Pangenomic Classification of Pituitary Neuroendocrine Tumors

Néou, Mario; Villa, Chiara; Armignacco, Roberta; Jouinot, Anne; Raffin-Sanson, Marie-Laure; Septier, Amandine; Letourneur, Franck; Diry, Ségolène; Diedisheim, Marc; Izaac, Brigitte; Gaspar, Cassandra; Perlemoine, Karine; Verjus, Victoria; Bernier, Michèle; Boulain, Anne; Émile, Jean-François; Bertagna, Xavier; Jaffrézic, Florence; Laloë, Dénis; Baussart, Bertrand; Bertherat, Jérôme; Gaillard, Stéphan; Assié, Guillaume

doi:10.2139/ssrn.3419077

Cited by 14 publications

(25 citation statements)

References 42 publications

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“…Furthermore, we found nearly one-third of SSTR2 -positive cases in GONA, which provided the evidence of 35±13% control ratio in non-functioning pituitary tumors by SSTR2 agonists ( 1 ). Combined with a low level of CDKN2A in GONA, Palbociclib-combined SSAs should be evaluated in future clinical trials.…”

Section: Discussionsupporting

confidence: 71%

“…The intensity score (0-3) was multiplied by the percentage of cells that stained with each level of intensity and the sum of these mathematical products was expressed as a score of 0-300. H score formula was calculated as: Strong intensity ( 3 ) x percentage + moderate intensity ( 2 ) x percentage + mild intensity ( 1 ) x percentage.…”

Section: Methodsmentioning

confidence: 99%

“…Pituitary neuroendocrine tumors (PitNETs) have five main histological subtypes: somatotroph, lactotroph, thyrotroph, corticotroph, and gonadotroph ( 1 ). Somatotroph adenomas (SOMA) are the primary cause of acromegaly, leading to severe complications such as hypertension, diabetes mellitus, cardiovascular disease, osteoarthritis, and sleep apnea ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

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CDKN2A (p16INK4A) affects the anti‑tumor effect of CDK inhibitor in somatotroph adenomas

Chen

Fang

et al. 2020

Int J Mol Med

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The altered cell cycle is associated with aberrant growth factor signaling in somatotroph adenoma, which is the primary cause of acromegaly. The aim of the present study was to investigate the pathological role of the INK4 family and evaluate the effectiveness of CDK4 inhibitor, palbociclib, in somatotroph adenoma. RNA-Seq, RT-PcR, and immunohistochemistry were applied to measure the levels and correlations of the INK4 family with angiogenesis, cdKs, EMT, and therapeutic targets. MTS, flow cytometry, and ELISA were used to investigate the bio-activity in GH3 and GT1-1 cell lines after palbociclib treatment. compared with lactotroph adenoma, gonadotroph adenoma, and corticotroph adenoma, somatotroph samples demonstrated higher expression of CDKN2A and SSTR2 but a lower expression of EGFR, CDK4, and CDH2 (P<0.05). CDKN2A positively correlates with SSTR2, and negatively with CDK4, EGFR, and CDH2. Patients with lower CDKN2A had larger tumor size (P=0.016) and more invasive potential (P=0.023). Palbociclib inhibited cell proliferation, induced G1 phase arrest, reduced GH/IGF-1 secretion of GH3 and GT1-1 cell lines (P<0.05), and had a more prominent role in GH3 cells (P<0.05). CDKN2A inhibited the bio-activity by modulating CDK4, and high CDKN2A predicted the insensitivity to CDK4 inhibitor, palbociclib, in somatotroph adenoma patients. In summary, the present study shows CDKN2A inhibited the bio-activity by modulating CDK4, and high CDKN2A predicts the insensitivity to CDK4 inhibitor, Palbociclib, in somatotroph adenoma patients.

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Section: Discussionsupporting

confidence: 71%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CDKN2A (p16INK4A) affects the anti‑tumor effect of CDK inhibitor in somatotroph adenomas

Chen

Fang

et al. 2020

Int J Mol Med

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“…Low E‐cadherin expression in our study was the most sensitive and specific feature of SGST defined by the presence of fibrous bodies: in the non‐SGST group, only one case (1.5%) showed complete absence of E‐cadherin compared to 30 in the SGST group (71.4%). Three plurihormonal Pit1 + tumours showed absence of E‐cadherin as well; it is unknown whether this illustrates the general mechanisms (ie epithelial‐mesenchymal transition) responsible for the more aggressive behaviour of these tumours or reflects the possible relationship between the two entities, as suggested recently 26 . The predictive value of E‐cadherin for SSA treatment has been suggested in two studies 11,12 .…”

Section: Discussionmentioning

confidence: 81%

“…9,21-25 for the more aggressive behaviour of these tumours or reflects the possible relationship between the two entities, as suggested recently. 26 The predictive value of E-cadherin for SSA treatment has been suggested in two studies. 11,12 However, based on the results, we do not consider E-cadherin to be an independent predictor, but rather a surrogate marker of the SGST subtype: this is illustrated by the fact that all the SGST in the poor response subgroup (8/10) showed no expression of E-cadherin (H-score 0) while two remaining non-SGST tumours showed E-cadherin expression comparable to the subgroup with good response (H-scores 104 and 155).…”

Section: Discussionmentioning

confidence: 99%

Predictive and prognostic significance of tumour subtype, SSTR1‐5 and e‐cadherin expression in a well‐defined cohort of patients with acromegaly

Soukup

Hornychová

Manethova

et al. 2021

J Cellular Molecular Medi

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In somatotroph pituitary tumours, somatostatin analogue (SSA) therapy outcomes vary throughout the studies. We performed an analysis of cohort of patients with acromegaly from the Czech registry to identify new prognostic and predictive factors. Clinical data of patients were collected, and complex immunohistochemical assessment of tumour samples was performed (SSTR1‐5, dopamine D2 receptor, E‐cadherin, AIP). The study included 110 patients. In 31, SSA treatment outcome was evaluated. Sparsely granulated tumours (SGST) differed from the other subtypes in expression of SSTR2A, SSTR3, SSTR5 and E‐cadherin and occurred more often in young. No other clinical differences were observed. Trouillas grading system showed association with age, tumour size and SSTR2A expression. Factors significantly associated with SSA treatment outcome included age, IGF1 levels, tumour size and expression of E‐cadherin and SSTR2A. In the group of SGST, poor SSA response was observed in younger patients with larger tumours, lower levels of SSTR2A and higher Ki67. We observed no relationship with expression of other proteins including AIP. No predictive value of E‐cadherin was observed when tumour subtype was considered. Multiple additional factors apart from SSTR2A expression can predict treatment outcome in patients with acromegaly.

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Double adenomas of the pituitary reveal distinct lineage markers, copy number alterations, and epigenetic profiles

et al. 2021

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Purpose Pituitary adenoma (PA) constitutes the third most common intracranial neoplasm. The mostly benign endocrine lesions express no hormone (null cell PA) or the pituitary hormone(s) of the cell lineage of origin. In 0.5–1.5% of surgical specimens and in up to 10% of autopsy cases, two or three seemingly separate PA may coincide. These multiple adenomas may express different hormones, but whether or not expression of lineage-restricted transcription factors and molecular features are distinct within multiple lesions remains unknown. Methods Searching the data bank of the German Pituitary Tumor Registry 12 double pituitary adenomas with diverse lineage were identified among 3654 adenomas and 6 hypophyseal carcinomas diagnosed between 2012 and 2020. The double adenomas were investigated immunohistochemically for expression of hormones and lineage markers. In addition, chromosomal gains and losses as well as global DNA methylation profiles were assessed, whenever sufficient material was available (n = 8 PA). Results In accordance with the literature, combinations of GH/prolactin/TSH–FSH/LH adenoma (4/12), GH/prolactin/TSH–ACTH adenoma (3/12), and ACTH–FSH/LH adenoma (3/12) were observed. Further, two out of 12 cases showed a combination of a GH/prolactin/TSH adenoma with a null-cell adenoma. Different expression pattern of hormones were confirmed by different expression of transcription factors in 11/12 patients. Finally, multiple lesions that were molecularly analysed in 4 patients displayed distinct copy number changes and global methylation pattern. Conclusion Our data confirm and extend the knowledge on multiple PA and suggest that such lesions may origin from distinct cell types.

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Pangenomic Classification of Pituitary Neuroendocrine Tumors

Cited by 14 publications

References 42 publications

CDKN2A (p16INK4A) affects the anti‑tumor effect of CDK inhibitor in somatotroph adenomas

CDKN2A (p16INK4A) affects the anti‑tumor effect of CDK inhibitor in somatotroph adenomas

Predictive and prognostic significance of tumour subtype, SSTR1‐5 and e‐cadherin expression in a well‐defined cohort of patients with acromegaly

Double adenomas of the pituitary reveal distinct lineage markers, copy number alterations, and epigenetic profiles

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