Genome-wide methylation profiling differentiates benign from aggressive and metastatic pituitary neuroendocrine tumors

Aggressive pituitary neuroendocrine tumors (PitNETs)/adenomas are characterized by progressive growth despite surgery and all standard medical therapies and radiotherapy. A subset will metastasize to the brain and/or distant locations and are termed metastatic PitNETs (pituitary carcinomas). Studies of potential prognostic markers have been limited due to the rarity of these tumors. A few recurrent somatic mutations have been identified, and epigenetic alterations and chromosomal rearrangements have not been explored in larger cohorts of aggressive and metastatic PitNETs. In this study, we performed genome-wide methylation analysis, including copy-number variation (CNV) calculations, on tumor tissue specimens from a large international cohort of 64 patients with aggressive (48) and metastatic (16) pituitary tumors. Twelve patients with non-invasive pituitary tumors (Knosp 0-2) exhibiting an indolent course over a 5 year follow-up served as controls. In an unsupervised hierarchical cluster analysis, aggressive/metastatic PitNETs clustered separately from benign pituitary tumors, and, when only specimens from the first surgery were analyzed, three separate clusters were identified: aggressive, metastatic, and benign PitNETs. Numerous CNV events affecting chromosomal arms and whole chromosomes were frequent in aggressive and metastatic, whereas benign tumors had normal chromosomal copy numbers with only few alterations. Genome-wide methylation analysis revealed different CNV profiles and a clear separation between aggressive/metastatic and benign pituitary tumors, potentially providing biomarkers for identification of these tumors with a worse prognosis at the time of first surgery. The data may refine follow-up routines and contribute to the timely introduction of adjuvant therapy in patients harboring, or at risk of developing, aggressive or metastatic pituitary tumors.

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Publication Details

Journal
Acta Neuropathologica
Published
2024-11-23
DOI
https://doi.org/10.1007/s00401-024-02836-5
Citations
8
Primary Topic
Neuroendocrine Tumor Research Advances
Type
article
Field-Weighted Citation Impact
3.09

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article

Genome-wide methylation profiling differentiates benign from aggressive and metastatic pituitary neuroendocrine tumors

Maria Petersson, Zita Reisz, Stephan Petersenn, Jelena Jotanovic et al.
8 citations
Acta Neuropathologica
Neuroendocrine Tumor Research Advances
3.09
article

Genome-wide methylation profiling differentiates benign from aggressive and metastatic pituitary neuroendocrine tumors

Maria Petersson, Zita Reisz, Stephan Petersenn, Jelena Jotanovic, Paul Benjamin Loughrey, Pia Burman, Olivera Casar‐Borota, Henning B. Boldt, Wolfgang Saeger, Maria Rosa Terreni, John R. Lindsay, Vera Popović, Óskar Ragnarsson, Antonia Jakovčević, Emilija Manojlović-Gačić, Olli Tynninen, Dominique Maiter, Bertil Ekman, Ivana Kraljević, Marco Losa, Jens Pahnke, Marianne Andersen, Mark Burton, David Scheie, Ansgar Heck, Camilla Schalin‐Jäntti, Thomas Olsson Bontell, Maria Maksymowicz, Ben Whitelaw, Jacek Kunicki, Ulla Feldt‐Rasmussen, Daniel Bengtsson, Britt Edén Engström, Jens Otto Lunde Jørgensen, Åse Krogh Rasmussen
article en
8 citations

Abstract

Aggressive pituitary neuroendocrine tumors (PitNETs)/adenomas are characterized by progressive growth despite surgery and all standard medical therapies and radiotherapy. A subset will metastasize to the brain and/or distant locations and are termed metastatic PitNETs (pituitary carcinomas). Studies of potential prognostic markers have been limited due to the rarity of these tumors. A few recurrent somatic mutations have been identified, and epigenetic alterations and chromosomal rearrangements have not been explored in larger cohorts of aggressive and metastatic PitNETs. In this study, we performed genome-wide methylation analysis, including copy-number variation (CNV) calculations, on tumor tissue specimens from a large international cohort of 64 patients with aggressive (48) and metastatic (16) pituitary tumors. Twelve patients with non-invasive pituitary tumors (Knosp 0-2) exhibiting an indolent course over a 5 year follow-up served as controls. In an unsupervised hierarchical cluster analysis, aggressive/metastatic PitNETs clustered separately from benign pituitary tumors, and, when only specimens from the first surgery were analyzed, three separate clusters were identified: aggressive, metastatic, and benign PitNETs. Numerous CNV events affecting chromosomal arms and whole chromosomes were frequent in aggressive and metastatic, whereas benign tumors had normal chromosomal copy numbers with only few alterations. Genome-wide methylation analysis revealed different CNV profiles and a clear separation between aggressive/metastatic and benign pituitary tumors, potentially providing biomarkers for identification of these tumors with a worse prognosis at the time of first surgery. The data may refine follow-up routines and contribute to the timely introduction of adjuvant therapy in patients harboring, or at risk of developing, aggressive or metastatic pituitary tumors.

Acta NeuropathologicaVol. 148(1)
Linköping University (SE), Uppsala University (SE), University of Copenhagen (DK), Queen's University Belfast (GB), Oslo University Hospital (NO), Belfast Health and Social Care Trust (GB), Cliniques Universitaires Saint-Luc (BE), Karolinska University Hospital (SE), University of Helsinki (FI), Uppsala University Hospital (SE), University of Ulster (GB), University Hospital Centre Zagreb (HR), Vita-Salute San Raffaele University (IT), Universität Hamburg (DE), University of Southern Denmark (DK), University of Zagreb (HR), University of Oslo (NO), Lund University (SE), Helsinki University Hospital (FI), Sahlgrenska University Hospital (SE), Odense University Hospital (DK), Aarhus University Hospital (DK), Copenhagen University Hospital (DK), Rigshospitalet (DK), Karolinska Institutet (SE), University of Belgrade (RS), University Medical Center Hamburg-Eppendorf (DE), King's College Hospital NHS Foundation Trust (GB), Royal Victoria Hospital (GB), Skåne University Hospital (SE), Landstinget i Kalmar län (SE), The Maria Sklodowska-Curie National Research Institute of Oncology (PL), Istituti di Ricovero e Cura a Carattere Scientifico (IT), University of Duisburg-Essen (DE), University of Gothenburg (SE)
Pfizer, Finska Läkaresällskapet, European Society of Endocrinology, Lunds Universitet, Akademiska Sjukhuset, Uppsala Universitet, Kirsten og Freddy Johansens Fond, Svenska Läkaresällskapet, Region Uppsala
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Openalex Percentile: Top 7%
Neuroendocrine Tumor Research Advances
3.09
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